1,2,3,4-tetrahydroisoquinoline derivatives

ABSTRACT

The invention relates to novel 1,2,3,4-tetrahydroisochinoline derivatives of formula (I) and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as orexin receptor antagonists.

This is a national stage application of International ApplicationPCT/EP01/02733, filed Mar. 12, 2001, which was published under PCTArticle 21(2) as PCT Publication No. WO 01/68609 in English, and whichclaims the benefit of International Application PCT/EP00/02245 filedMar. 14, 2000. Both International Applications PCT/EP01/02733 andPCT/EP00/02245 are hereby incorporated by reference in their entireties.

The present invention relates to novel 1,2,3,4-tetrahydroisoquinolinederivatives of the general formula I and their use as pharmaceuticals.The invention also concerns related aspects including processes for thepreparation of the compounds, pharmaceutical compositions containing oneor more compounds of formula I, and especially their use as orexinreceptor antagonists.

The orexins (hypocretins) comprise two neuropeptides produced in thehypothalamus: the orexin A (OX-A) (a 33 aminoacid peptide) and theorexin B (OX-B) (a 28 aminoacid peptide) (Sakurai T. et al., Cell, 1998,92, 573-585). Orexins are found to stimulate food consumption in ratssuggesting a physiological role for these peptides as mediators in thecentral feedback mechanism that regulates feeding behavior (Sakurai T.et al., Cell, 1998, 92, 573-585). On the other hand, it was alsoproposed that orexins regulate states of sleep and wakefulness openingpotentially novel therapeutic approaches for narcoleptic patients(Chemelli R. M. et al., Cell, 1999, 98, 437-451). Two orexin receptorshave been cloned and characterized in mammals which belong to theG-protein coupled receptor superfamily (Sakurai T. et al., Cell, 1998,92, 573-585), the orexin-l receptor (OX₁) which is selective for OX-Aand the orexin-2 receptor (OX₂) which is capable to bind OX-A as well asOX-B.

Orexin receptors are found in the mammalian host and may be responsiblefor many biological functions such as pathologies including, but notlimited to, depression; anxiety; addictions; obsessive compulsivedisorder; affective neurosis; depressive neurosis; anxiety neurosis;dysthymic disorder; behaviour disorder; mood disorder; sexualdysfunction; psychosexual dysfunction; sex disorder; schizophrenia;manic depression; delerium; dementia; severe mental retardation anddyskinesias such as Huntington's disease and Tourette syndrome; feedingdisorders such as anorexia, bulimia, cachexia and obesity; diabetes;appetite/taste disorders; vomiting/nausea; asthma; cancer; Parkinson'sdisease; Cushing's syndrome/disease; basophil adenoma; prolactinoma;hyperprolactinemia; hypopituitarism; hypophysis tumor/adenoma;hypothalamic diseases; inflammatory bowel disease; gastric diskinesia;gastric ulcus; Froehlich's syndrome; adrenohypophysis disease;hypophysis disease; pituitary growth hormone; adrenohypophysishypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism;Kallman's syndrome (anosmia, hyposmia); functional or psychogenicamenorrhea; hypopituitarism; hypothalamic hypothyroidism;hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia;hypothalamic disorders of growth hormone deficiency; idiopathic growthdeficiency; dwarfism; gigantism; acromegaly; disturbed biological andcircadian rhythms; sleep disturbances associated with deseases such asneurological disorders, neuropathic pain and restless leg syndrome; heatand lung diseases, acute and congestive heart failure; hypotension;hypertension; urinary retention; osteoporosis; angina pectoris;myocardinal infarction; ischaemic or haemorrhagic stroke; subarachnoidhaemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronicrenal failure; renal disease; impaired glucose tolerance; migraine;hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such ashyperalgesia, causalgia, and allodynia; acute pain; burn pain; a typicalfacial pain; neuropathic pain; back pain; complex regional pain syndromeI and II; arthritic pain; sports injury pain; pain related to infectione.g. HIV, post-chemotherapy pain; post-stroke pain; post-operative pain;neuralgia; conditions associated with visceral pain such as irritablebowel syndrome, migraine and angina; urinary bladder incontinence e.g.urge incontinence; tolerance to narcotics or withdrawal from narcotics;sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lagsyndrome; and neurodegerative disorders including nosological entitiessuch as disinhibition-dementia-parkinsonism-amyotrophy complex;pallido-ponto-nigral degeneration epilepsy; seizure disorders and otherdiseases related to orexin.

The present invention provides 1,2,3,4-tetrahydroisoquinolinederivatives which are non-peptide antagonists of human orexin receptors,in particular OX₁ receptors. In particular, these compounds are ofpotential use in the treatment of obesity and/or sleep disorders.

So far not much is known about low molecular weight compounds which havea potential to antagonise either specifically OX₁ or OX₂ or bothreceptors at the same time. Recently WO 9909024 has been publishedwherein phenylurea and phenylthiourea derivatives as OX₁ antagonists aredisclosed. Also quite recently WO 9958533 has been published disclosingthe same type of compounds which are again

described as being preferably OX₁ receptor antagonists. The novelcompounds of the present invention belong to an entirely different classof low molecular weight compounds as compared to all prior art orexinreceptor antagonists so far published.

The present invention relates to novel 1,2,3,4-tetrahydroisoquinolinederivatives of the general formula (I).

wherein:

R¹, R², R³, R⁴ independently represent cyano, nitro, halogen, hydrogen,hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy,trifluoromethyl, trifluoromethoxy, cycloalkyloxy, aryloxy, aralkyloxy,heterocyclyloxy, heterocyclylalkyloxy, R¹¹CO—, NR¹²R¹³CO—, R¹²R¹³N—,R¹¹OOC—, R¹¹SO₂NH— or R¹⁴—CO—NH— or R² and R³ together as well as R¹ andR² together and R³ and R⁴ together may form with the phenyl ring a five,six or seven-membered ring containing one or two oxygen atoms;

R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ independently represent hydrogen, aryl, aralkyl,lower alkyl, lower alkenyl, trifluoromethyl, cycloalkyl, heterocyclyl orheterocyclyl-lower alkyl;

R¹¹ represents lower alkyl, aryl, aralkyl, heterocyclyl orheterocyclyl-lower alkyl;

R¹² and R¹³ independently represent hydrogen, alkyl, cycloalkyl, aryl,aralkyl, heterocyclyl or heterocyclyl-lower alkyl;

R¹⁴ represents alkyl, aryl, cycloalkyl, heterocyclyl, R¹²R¹³N— or R¹¹O—.

The compounds of formula I can contain one or more asymmetric centresand can be present in the form of optically pure enantiomers, mixturesof enantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates, mixture of diastereoisomeric racemates, or meso forms andpharmaceutically acceptable salts thereof.

In the present description the term “lower alkyl”, alone or incombination, signifies a straight-chain or branched-chain alkyl groupwith 1 to 8 carbon atoms, preferably a straight or branched-chain alkylgroup with 1-5 carbon atoms. Examples of straight-chain and branchedC₁-C₈ alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, pentyl,hexyl, heptyl, octyl, isobutyl tert-butyl, the isomeric pentyls, theisomeric hexyls, the isomeric heptyls and the isomeric octyls,preferably methyl, ethyl, propyl, isopropyl, butyl, 2-butyl, tert-butyland pentyl.

The term “lower alkenyl”, alone or in combination, signifies astraight-chain or branched-chain alkenyl group with 2 to 5 carbon atoms,preferably allyl and vinyl.

The term “lower alkoxy”, alone or in combination, signifies a group ofthe formula alkyl-O— in which the term “alkyl” has the previously givensignificance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy and tert-butoxy, preferably methoxy and ethoxy.

Lower alkenyloxy groups are preferably vinyloxy and allyloxy.

The term “cycloalkyl”, alone or in combination, signifies a cycloalkylring with 3 to 8 carbon atoms and preferably a cycloalkyl ring with 3 to6 carbon atoms. Examples of C₃-C₈ cycloalkyl are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl,preferably cyclopropyl, cyclohexyl and particularly cyclohexyl or loweralkyl substituted cycloalkyl which may preferably be substituted withlower alkyl such as methyl-cyclopropyl, dimethyl-cyclopropyl,methyl-cyclobutyl, methyl-cyclopentyl, methyl-cyclohexyl,dimethyl-cyclohexyl,

The term “aryl”, alone or in combination, signifies a phenyl or naphthylgroup which optionally carries one or more substituents, preferably oneor two substituents, each independently selected from cyano, halogen,hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy,nitro, trifluoromethyl, trifluoromethoxy, amino, carboxy and the like,such as phenyl, p-tolyl, 4-methoxyphenyl, 4-tert-butoxyphenyl4-fluorophenyl, 2-chlorophenyl, 4-hydroxyphenyl, 1-naphthyl and2-naphthyl. Preferred are carboxyphenyl, lower alkoxy-phenyl,hydroxyphenyl and particularly phenyl.

The term “aralkyl”, alone or in combination, signifies an alkyl orcycloalkyl group as previously defined in which one hydrogen atom hasbeen replaced by an aryl group as previously defined. Preferred arebenzyl and benzyl substituted in the phenyl ring with hydroxy, loweralkyl, lower alkoxy or halogen preferably chlorine. Particularlypreferred is benzyl.

For the term “heterocyclyl” and “heterocyclyl-lower alkyl”, theheterocyclyl group is preferably a 5- to 10-membered monocyclic orbicyclic ring, which may be saturated, partially unsaturated or aromaticcontaining for example 1, 2 or 3 heteroatoms selected from oxygen,nitrogen and sulphur which may be the same or different. Example of suchheterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, pyridyl pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl,isoquinolyl, thienyl, thiazolyl, isothiazolyl, furyl, imidazoyl,pyrazolyl, pyrrolyl, indazolyl, indolyl, isoindolyl, isoxazolyl,oxazolyl, quinoxalinyl, phthalazinyl, cinnolinyl, dihydropyrrolyl,pyrrolidinyl, isobenzofuranyl, tetrahydrofuranyl, dihydropyranyl. Theheterocyclyl group may have up to 5, preferably 1, 2 or 3 optionalsubstituents. Examples of suitable substituents include halogen, lowerallyl, amino, nitro, cyano, hydroxy, lower alkoxy, carboxy and loweralkyloxy-carbonyls.

The term “halogen” signifies fluorine, chlorine, bromine or iodine andpreferably chlorine and bromine and particularly chlorine.

The term “carboxy”, alone or in combination, signifies a —COOH group.

A group of preferred compounds according to the present invention arecompounds of formula (I) wherein R², R³, R⁶, R⁷, R⁸ and R⁹ are hydrogen.Examples of preferred compounds are:

2-[1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

2-[1-(3,4-dimethoxy-benzyl)-8-(cyclopropyl-methoxy)-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

2-[1-(3,4-dimethoxy-benzyl)-8-(2-fluoro-ethoxy)-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

2-[1-(3,4-dimethoxy-benzyl)-8-(2,2-difluoro-ethoxy)-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

2-[1-(3,4-dimethoxy-benzyl)-8-ethoxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

2-[1-(3,4-dimethoxy-benzyl)-8-propoxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

2-[1-(3,4-dimethoxy-benzyl)-8-allyloxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

2-[1-(3,4-dimethoxy-benzyl)-8-isopropoxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

2-[1-(3,4-dimethoxy-benzyl)-5-propoxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

Another group of preferred compounds according to the present inventionare compounds of formula (II)

wherein:

R′¹ and R′² independently represent hydrogen, hydroxy, alkoxy,heteroaryloxy, carbamoyloxy or halogen or may form with the phenyl ringa five, six or seven membered-ring containing one or two oxygen atoms,

R′³, R′⁴, R′⁵ independently represent aryl, aralkyl, lower alkyl, loweralkenyl trifluoromethyl, cycloallyl, heterocyclyl or heterocyclyl-loweralkyl.

The compounds of formula (II) can contain one or more asymmetric centresand can be present in the form of optically pure enantiomers, mixturesof enantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates, mixture of diastereoisomeric racemates, or meso forms andpharmaceutically acceptable salts thereof

Examples of preferred compounds of formula (II) are:

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-naphthalen-1-ylmethyl-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methoxy-benzyl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(4-fluoro-benzyl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(6-methoxy-naphthalen-2-ylmethyl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(4-methoxy-naphthalen-2-ylmethyl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(3,6)-difluoro-benzyl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1-phenyl-ethyl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-3-ylmethyl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methyl-benzyl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(3-methyl-benzyl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-(pyrazin-2-yloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-(thiazol-2-yloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(5-methoxy-indan-1-yl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(6-methoxy-indan-1-yl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(6-methyl-indan-1-yl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(4-methyl-indan-1-yl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(6-methoxy-indan-1-yl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(6-methyl-indan-1-yl)-acetamide

2-{-[4-(pyrimidin-2-yloxy)-3-methoxy-benzyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-N-benzyl-acetamide

2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-(N,N-dimethylcarbamoyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-(3-fluoro-propoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-(2-fluoro-ethoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-(2,2-difluoro-ethoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-(but-2-oxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-(cyclopropyl-methoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-ethoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-propoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-allyloxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-isopropoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-(1-methyl-prop-2-oxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1S)-indan-1-yl]-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide

2-[(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin2-yl]-N-[(1S)-indan-1-yl]-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-ethoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-propoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-allyloxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide

N-benzyl-2-[1-(3,4-Dimethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-acetamide

2-[1-(3,4-Dimethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1S)-indan-1-yl]-acetamide

N-benzyl-2-[-(3,4-Diethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-H-isoquinolin-2-yl]-acetamide

2-[1-(3,4-Diethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide

2-[1-(3,4-Diethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-3-yl-methyl)-acetamide

2-[1-(3,4-Diethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-4-yl-methyl)-acetamide

2-[1-(3,4-Dichloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-3-yl-methyl)-acetamide

Examples of particularly preferred compounds of formula (II) are:

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-naphthalen-1-ylmethyl-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-pyrazin-2-yloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-(thiazol-2-yloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(5-methoxy-indan-1-yl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(6-methoxy-indan-1-yl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(6-methyl-indan-1-yl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(4-methyl-indan-1-yl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(6-methoxy-indan-1-yl)-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(6-methyl-indan-1-yl)-acetamide

2-{1-[4-(pyrimidin-2-yloxy)-3-methoxy-benzyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-N-benzyl-acetamide

2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-(N,N-dimethylcarbamoyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-(3-fluoro-propoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-(2-fluoro-ethoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-(2,2-difluoro-ethoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-(but-2-oxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-(cyclopropyl-methoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-ethoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-propoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-allyloxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-isopropoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-(1-methyl-prop-2-oxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1S)-indan-1-yl]-acetamide

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide

2-[(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1S)-indan-1-yl]-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-ethoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-propoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide

2-[1-(3,4-dimethoxy-benzyl)-7-allyloxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide

N-benzyl-2-[1-(3,4-Dimethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-acetamide

2-[1-(3,4-Dimethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1S)-indan-1-yl]-acetamide

N-benzyl-2-[1-(3,4-Diethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-acetamide

2-[1-(3,4-Diethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide

2-[1-(3,4-Diethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-3-yl-methyl)-acetamide

2-[1-(3,4-Diethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-4-yl-methyl)-acetamide

2-[1-(3,4-Dichloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-3-yl-methyl)-acetamide

Examples of physiologically usable or pharmaceutically acceptable saltsof the compounds of formula (I) are salts with physiologicallycompatible mineral acids such as hydrochloric acid, sulphuric orphosphoric acid; or with organic acids such as methanesulphonic acid,acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleicacid, tartaric acid, succinic acid or salicylic acid. The compounds offormula (I) with free carboxy groups can also form salts withphysiologically compatible bases.

Examples of such salts are alkali metal, alkali earth metal, ammoniumand alkylammoniumsalts such as Na, K, Ca or tetraalkylammonium salt. Thecompounds of formula (I) can also be present in the form of azwitterion.

The compounds of formula (I) can contain several asymmetric centres andcan be present in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diasteroisomericracemates or mixtures of diastereoisomeric racemates and the meso-forms.

Preferred compounds as described above have IC₅₀ values below 1000 nM;especially preferred compounds have IC₅₀ values below 100 nM which havebeen determinated with the FLIPR (Fluorometric Imaging Plates Reader)method described in the beginning of the experimental section.

The compounds of the general formula (I) and their pharmaceuticallyusable salts can be used for the treatment of diseases or disorderswhere an antagonist of a human orexin receptor is required such asobesity, diabetes, prolactinoma, narcolepsy, insomnia, sleep apnea,parasomnia, depression; anxiety, addictions, schizophrenia and dementia.

The compounds of formula (I) and their pharmaceutically usable salts areparticularly useful for the treatment of obesity and sleep disorders.

The compounds of formula (I) and their pharmaceutically usable salts canbe used as medicament (e.g. in the form of pharmaceutical preparations).The pharmaceutical preparations can be administered internally, such asorally (e.g. in the form of tablets, coated tablets, dragées, hard andsoft gelatine capsules, solutions, emulsions or suspensions), nasally(e.g. in the form of nasal sprays) or rectally (e.g. in the form ofsuppositories). However, the administration can also be effectedparentally, such as intramuscularly or intravenously (e.g. in the formof injection solutions).

The compounds of formula (I) and their pharmaceutically usable salts canbe processed with pharmaceutically inert, inorganic or organic adjuvantsfor the production of tablets, coated tablets, dragées, and hardgelatine capsules. Lactose, corn starch or derivatives thereof, talc,stearic acid or its salts etc. can be used, for example, as suchadjuvants for tablets, dragées, and hard gelatine capsules.

Suitable adjuvants for soft gelatine capsules, are, for example,vegetable oils, waxes, fats, semi-solid substances and liquid polyols,etc.

Suitable adjuvants for the production of solutions and syrups are, forexample, water, polyols, saccharose, invert sugar, glucose, etc.

Suitable adjuvants for injection solutions are, for example, water,alcohols, polyols, glycerol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for example, natural orhardened oils, waxes, fats, semi-solid or liquid polyols, etc.

Morever, the pharmaceutical preparations can contain preservatives,solubilizers, viscosity-increasing substances, stabilizers, wettingagents, emulsifiers, sweeteners, colorants, flavorants, salts forvarying the osmotic pressure, buffers, masking agents or antioxidants.They can also contain still other therapeutically valuable substances.The invention also relates to processes for the preparation of compoundsof Formula I.

The compounds of general formula (I) of the present invention areprepared according to the general sequence of reactions outlined in theschemes below, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰ are asdefined in formula (I) above. As the case may be any compound obtainedwith one or more optically active carbon atom may be resolved into pureenantiomers or diastereomers, mixtures of enantiomers or diastereomers,diastereomeric racemates and the meso-forms in a manner known per se.

The compounds obtained may also be converted into a pharmaceuticallyacceptable salt thereof in a manner known per se.

The compounds of formula (I) may be prepared as single compounds or aslibraries of compounds comprising at least 2, e.g. 5 to 1000 compoundsof formula (I).

Compound libraries may be prepared by a combinatorial approach or bymultiple parallel synthesis using solution phase chemistry.

For the combinatorial approach, the compounds of general formula (I)wherein R⁶, R⁷, R⁹ are hydrogen, are prepared using anUgi-three-components-condensation reaction (Ugi-3-CC) which involves theone-pot reaction between a 1,2,3,4-tetrahydroisoquinoline derivative, analdehyde and an isocyanide (Scheme 1).

Isocyanides not commercially available might be prepared from thecorresponding amines by N-formylation followed by treatment with POCl₃(see e.g. J. March, fourth edition, Wiley-Interscience publication, p.1042).

The compounds of the general formula (I) wherein R⁶ and R⁷ are hydrogen,may also be prepared by different procedures. The synthetic routedepends on the last chemical transformation which has to be carried out.

In all cases in which the coupling of the tetrahydroisoquinoline withthe amide side-chain is the final step the standard procedure shown in(Scheme 2) was followed. The tetrahydroisoquinolines as well as theamines (R⁹R¹⁰NH) could be either commercially available or synthesized.

Tetrahydroisoquinolines not commercially available might be preparedfrom the corresponding phenylethylamines by coupling with the desiredcarboxylic acid followed by treatment with POCl₃ and finally NaBH₄ (seeexperimental part). All aminoindan-derivatives were prepared by reactionof 1-indanones with O-methylhydroxylamine followed by reduction withborane-tetrahydrofuran complex (Vaccaro W. et al., J. Med. Chem., 1996,39, 1704-1719).

Compounds of general formula (I) wherein one substituent of the1-benzyl-tetrahydroisoquinoline scaffold is a carbamoyloxy-,heteroaryloxy- or alkoxy-residue (not methoxy) are synthesized accordingto (Scheme 3). The benzyl-protected phenols are prepared by theprocedure shown in (Scheme 2).

In the case R⁵ (general formula I) is a heterocyclyl-methyl substituentthe final step is the substitution of a mesylate function with thecorresponding nitrogen containing nucleophile according to (Scheme 4).The required starting material was synthesized by the same procedure asdescribed earlier (Scheme 2).

Stereochemically pure compounds of general formula I are obtained bykinetic resolution of the tetrahydroisoquinoline (Corrodi H., HardeggerE., Helv. Chim. Acta, 1956, 39, 889-897) and coupling of the pureenantiomer with the amide linker according to Scheme 2. Furthermore2-[(1S)-1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1S)-indan-1-yl]-acetamidecould also be obtained by crystallization of the diastereoisomericmixture of the two2-{1[R,S]-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-N-[(1S)-indan-1-yl]-acetamidesfrom methanol.

Experimental Section

I. Biology

Determination of OX₁ Receptor Antagonist Activity

The OX₁ receptor antagonist activity of the compounds of formula (I) wasdeterminated in accordance with the following experimental method.

Experimental Method:

Intracellular Calcium Measurements

Chinese hamster ovary (CHO) cells expressing the human orexin-1 receptorand the human orexin-2 receptor, respectively, were grown in culturemedium (Ham F-12 with L-Glutamine) containing 300 μg/ml G418, 100 U/mlpenicillin, 100 μg/ml streptomycin and 10% inactivated foetal calf serum(FCS).

The cells were seeded at 80,000 cells/well into 96-well black clearbottom sterile plates (Costar) which had been precoated with 1% gelatinein Hanks' Balanced Salt Solution (HBSS). All reagents were from GibcoBRL.

The seeded plates were incubated overnight at 37° C. in 5% CO₂.

Human orexin-A as an agonist was prepared as 1 mM stock solution inmethanol:water (1:1), diluted in HBSS containing 0.1% bovine serumalbumin (BSA) and 2 mM HEPES for use in the assay at a finalconcentration of 10 nM.

Antagonists were prepared as 10 mM stock solution in DMSO, then dilutedin 96-well plates, first in DMSO, then in HBSS containing 0.1% bovineserum albumin (BSA) and 2 mM HEPES.

On the day of the assay, 100 μl of loading medium (HBSS containing 1%FCS, 2 mM HEPES, 5 mM probenecid (Sigma) and 3 μM of the fluorescentcalcium indicator fluo-3 AM (1 mM stock solution in DMSO with 10%pluronic acid) (Molecular Probes) was added to each well.

The 96-well plates were incubated for 60 min at 37° C. in 5% CO₂. Theloading solution was then aspirated and cells were washed 3 times with200 μl HBSS containing 2.5 mM probenecid, 0.1% BSA, 2 mM HEPES. 100 μlof that same buffer was left in each well. Within the FluorescentImaging Plate Reader (FLIPR, Molecular Devices), antagonists were addedto the plate in a volume of 50 μl, incubated for 20 min and finally 100μl of agonist was added. Fluorescence was measured for each well at 1second intervals, and the height of each fluorescence peak was comparedto the height of the fluorescence peak induced by 10 nM orexin-A withbuffer in place of antagonist. For each antagonist, IC₅₀ value (theconcentration of compound needed to inhibit 50% of the agonisticresponse) was determined.

II. Chemistry

The following examples illustrate the preparation of pharmacologicallyactive compounds of the invention but do not at all limit the scopethereof. All temperatures are stated in ° C.

All hydrochloride salts were prepared by dissolving the free-base indichloromethane and treating with an excess of ethereal HCl (2M).

General Procedures:

A. General Procedure A:

1-[(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-aceticacid benzyl ester

To a white suspension of1-(4,5-dimethoxybenzyl)6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-hydrochloride(1 g, 2.632 mmol) in a mixture of toluene/DMF (9/1) (10 ml), were addedtriethylamine (1.1 ml, 7.896 mmol) and chlorobenzylacetate (440 μl,2.895 mmol). The reaction mixture was stirred at reflux under argon for20 h. After cooling, the mixture was diluted in CH₂Cl₂ and washed withwater.

The aqueous phase was extracted twice with CH₂Cl₂, the combined organicphases were dried over anhydrous MgSO₄, filtered and concentrated togive a crude brown-orange oil. Flash chromatography (AcOEt/hexane 1/1)gave 1.15 g (89%) of the title product as a brown-orange oil.

TLC (AcOEt/hexane: 1/1): R_(f)=0.55.

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.16 min. m/z=492 (M+1).

1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-(3,4-dihydro-1H-isoquinolin-2-yl)-aceticacid.

To a solution of1-[(3,4-dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-aceticacid benzyl ester (1.15 g, 2.34 mmol) in dry AcOEt (20 ml) was added inone portion Pd-C 10% (250 mg). The resulting black suspension washydrogenated at normal pressure and room temperature for 20 h. Themixture was then filtered over celite and concentrated in vacuo to givebrown crystals.

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.34 min. m/z=402 (M+1).

EXAMPLE 1

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide

To a solution of1-(4,5-dimethoxybenzyl)-6,7-dimethoxy-(3,4-dihydro-1H-isoquinolin-2-yl)-aceticacid (100 mg, 0.249 mmol) in 4 ml of dry DMF, were added 129.6 mg (0.249mmol) of PyBOP, 29.9 μl (0.226 mmol) of benzylamine and dropwise 110 μl(0.521 mmol) of diisopropylethylamine (Hünig's base). The mixturereaction was stirred at RT under argon for 20 h. The mixture was thendissolved in CH₂Cl₂ and washed with water. The aqueous phase wasextracted twice with CH₂Cl₂, the combined organic extracts were driedover MgSO₄, filtered and concentrated to give a crude brown residue.Flash chromatography (AcOEt/hexane 8/2) gave 126 mg (94%) of the titlecompound as a brown viscous oil.

TLC (AcOEt/hexane: 8/2): R_(f)=0.65.

LC-MS MeCN/H₂O: 1/1): R_(t)=4.83 min. m/z=491(M+1).

EXAMPLE 2

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-naphthalen-1-ylmethyl-acetamide

In analogy to Example 1 but for the final step, reaction of1-(4,5-dimethoxybenzyl)-6,7-dimethoxy-(3,4-dihydro-1H-isoquinolin-2-yl)-aceticacid with 1-naphthlalenemethylamine to give the title compound as thefree-base (brown viscous oil) and the hydrochloride salt (browncrystals)

—TLC (AcOEt): R_(f)=0.55.

—LC-MS MeCN/H₂O: 1/1): R_(t)=5.97 min. m/z=541(M+1).

EXAMPLE 3

2-[1-(3,4-Dimethoxy-benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(6-methoxy-naphthalen-2-ylmethyl)-acetamide

In analogy to Example 1 but for the final step, reaction of1-(4,5-dimethoxybenzyl)-6,7-dimethoxy-(3,4-dihydro-1H-isoquinolin-2-yl)-aceticacid with 6-methoxynaphthalene-2-methylamine to give the title compoundas the free-base (brown oil).

—TLC (AcOEt): R_(f)=0.40 —LC-MS (MeCN/H₂O: 1/1): R_(t)=4.68 min.m/z=571(M+1).

2-(3-Bromo-4-methoxy-phenyl)-N-[2-(3,4-dimethoxy)-ethyl]-acetamide

LC-MS (MeCN/H₂O: 1/1): R_(t) 4.28 min, 409 (M+1, ES+).

N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-2-(3,4-dimethyl-phenyl)-acetamide

LC-MS (MeCN/H₂O: 1/1): R_(t) 4.36 min, 328 (M+1, ES+).

2-(3,4-Diethyl-phenyl)-N-[2-(3,4-dimethoxy)-ethyl]-acetamide

LC-MS (MeCN/H₂O: 1/1): R_(t) 4.18 min, 356 (M+1, ES+).

2-(3,4-Dichloro-phenyl)-N-[2-(3,4-dimethoxy)-ethyl]-acetamide

LC-MS (MeCN/H₂O: 1/1): R_(t) 4.12 min, 369 (M+1, ES+).

1-(4-Bromo-3-methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

LC-MS (MeCN/H₂O: 1/1): R_(t) 2.96 min, 393 (M+1, ES+).

1-(3,4-Dimethyl-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

LC-MS (MeCN/H₂O: 1/1): R_(t) 3.19 min, 312 (M+1, ES+).

1-(3,4-Diethyl-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

LC-MS (MeCN/H₂O: 1/1): R_(t) 2.25 min, 340 (M+1, ES+).

1-(3,4-Dichloro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline

LC-MS (MeCN/H₂O: 1/1): R_(t) 3.20 min, 353 (M+1, ES+).

1-[(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl]-phenyl-aceticacid methyl ester

To a white suspension of1-(4,5-dimethoxybenzyl)6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-hydrochloride(5 g, 0.013 mol) in dry toluene (50 ml), were added triethylamine (5.5ml, 0.039 mol) and bromo-phenyl-acetic acid methyl ester (2.07 ml, 0.013mol). The reaction mixture was stirred at reflux under argon for 20 h.After cooling, the mixture was diluted in CH₂Cl₂ and washed with water.The aqueous phase was extracted twice with CH₂Cl₂, the combined organicphases were dried over anhydrous MgSO₄, filtered and concentrated togive a crude brown-orange oil. Flash chromatography (AcOEt/hexane 1/1)gave 5.85 g (90%) of the title product as a brown-orange oil.

TLC (AcOEt/hexane: 1/1): R_(f)=0.55.

LC-MS (MeCN/H₂O: 1/1): R_(t) 4.00 min and R_(t) 4.36 min, 492 (M+1,ES+).

1-[(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl]-phenyl-aceticacid

To a solution of1-[(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl]-phenyl-aceticacid methyl ester (5.85 g, 0.011 mmol) in a mixture dioxane/MeOH (4/3)(160 ml) was added dropwise 2M NaOH_((aq)) (81 ml). The resultingmixture was stirred at RT for 20 h under nitrogen. The mixture was thenconcentrated in vacuo, combined with water and AcOEt. The aqueous phasewas acidified until pH 1 with 2N HCl, extracted three times with withCH₂Cl₂, the combined organic phases were dried over anhydrous MgSO₄,filtered and concentrated to give the titled product (5.55 g, 97%) asyellow-green crystals.

LC-MS (MeCN/H₂O: 1/1): R_(t) 3.62 min and R_(t) 3.65 min, 478 (M+1,ES+).

EXAMPLE 4

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl]-N-indan-1-yl-2-phenyl-acetamide:

To a solution of1-[(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl]-phenyl-aceticacid (100 mg, 0.209 mmol) in 5 ml of dry DMF, were added PyBOP (109 mg,0.209 mmol), 1-aminoindane (32.3 mg, 0.19 mmol) and dropwisediisopropylethylamine (Hünig's base). (75 μl, 0.437 mmol). The mixturereaction was stirred at RT under argon for 20 h. The mixture was thendissolved in CH₂Cl₂ and washed with water. The aqueous phase wasextracted twice with CH₂Cl₂, the combined organic extracts were driedover MgSO₄, filtered and concentrated to give a crude brown residue.Flash chromatography (AcOEt) gave 72 mg (64%) of the title compound as apale brown oil.

TLC (AcOEt): R_(f)=0.65.

LC-MS (MeCN/H₂O: 1/1): R_(t) 4.35 min and R_(t) 4.60 min, 593 (M+1,ES+).

EXAMPLE 5

N-Butyl-2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-phenyl-acetamide

prepared by reaction of1-[(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl]-phenyl-aceticacid with n-butylamine.

LC-MS (MeCN/H₂O: 1/1): R_(t) 4.09 min 533 (M+1, ES+).

1-[(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl]-pyrimidin-aceticacid ethyl ester

To a white suspension of1-(4,5-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-hydrochloride(1.65 g, 4.36 mmol) in dry DMF (5 ml), were added triethylamine (1.82ml, 0.013 mol) and bromo-pyrimidin-acetic acid ethyl ester (1.07 g, 4.36mmol). The reaction mixture was stirred at reflux under argon for 20 h.After cooling, the mixture was diluted in AcOEt and washed with water.The aqueous phase was extracted twice with CH₂Cl₂, the combined organicphases were dried over anhydrous AcOEt, filtered and concentrated togive a crude brown-orange oil. Flash chromatography (AcOEt) gave 1.4 g(63%) of the title product as a brown-orange oil.

TLC (AcOEt): R_(f)=0.55.

LC-MS (MeCN/H₂O: 1/1): R_(t) 4.54 min and R_(t) 4.69 min, 508 (M+1,ES+).

1-[(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl]-pyrimidin-aceticacid

To a solution of1-[(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl]-pyrimidin-aceticacid ethyl ester (1.4 g, 2.75 mmol) in a mixture dioxane/MeOH (4/3) (35ml) was added dropwise 2M NaOH_((aq)) (24 ml). The resulting mixture wasstirred at RT for 20 h under nitrogen. The mixture was then concentratedin vacuo, combined with water and AcOEt. The aqueous phase was acidifieduntil pH 1 with 2N HCl, extracted three times with with CH₂Cl₂, thecombined organic phases were dried over anhydrous MgSO₄, filtered andconcentrated to give the titled product (1.23 g, 93%) as yellow-greencrystals.

LC-MS (MeCN/H₂O: 1/1): R_(t) 3.11 min and R_(t) 3.24 min, 480 (M+1,ES+).

EXAMPLE 6

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl]-2-N-indan-2-yl-2-pyrimidin-5-yl-acetamide

prepared by reaction of1-[(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl]-pyrimidin-aceticacid with 2-aminoindane hydrochloride.

LC-MS (MeCN/H₂O: 1/1): R_(t) 4.64 min and R_(t) 4.83 min, 595 (M+1,ES+).

EXAMPLE 7

N-benzyl-2-[1-(3,4-Dimethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-acetamide:

prepared by reaction of1-(3,4-dimethyl-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with benzylamine.

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.35 min, 459 (M+1, ES+).

EXAMPLE 8

2-[1-(3,4-Dimethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-indan-1-yl-acetamide:

prepared by reaction of1-(3,4-dimethyl-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 1-aminoindane.

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.47 min, 485(M+1, ES+).

EXAMPLE 9

2-[1-(3,4-Dimethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-pyridin-2-yl-acetamide:

prepared by reaction of1-(3,4-dimethyl-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 2-picolylamine.

LC-MS (MeCN/H₂O: 1/1): R_(t)=2.99 min, 460 (M+1, ES+).

EXAMPLE 10

2-[1-(3,4-Dimethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-pyridin-3-yl-acetamide:

prepared by reaction of1-(3,4-dimethyl-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 3-picolylamine.

LC-MS (MeCN/H₂O: 1/1): R_(t)=2.61 min, 460 (M+1, ES+).

EXAMPLE 11

N-benzyl-2-[1-(3,4-Diethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-acetamide:

prepared by reaction of1-(3,4-diethyl-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with benzylamine.

LC-MS (MeCN/H₂O: 1/1): R_(t)=4.35 min, 459 (M+1, ES+).

EXAMPLE 12

2-[1-(3,4-Diethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-diethyl-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 2-picolylamine.

LC-MS (MeCN/H₂O: 1/1): R_(t)=2.87 min, 488 (M+1, ES+).

EXAMPLE 13

2-[1-(3,4-Diethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-3-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-diethyl-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 3-picolylamine.

LC-MS (MeCN/H₂O: 1/1): R_(t)=2.85 min. 488 (M+1, ES+).

EXAMPLE 14

2-[1-(3,4-Diethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-4-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-diethyl-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 4-picolylamine.

LC-MS MeCN/H₂O: 1/1): R_(t)=2.71 min. 488 (M+1, ES+).

EXAMPLE 15

2-[1-(3,4-Dichloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl-acetamide:

prepared by reaction of1-(3,4-dichloro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 2-picolylamine.

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.72 min, 501 (M+1, ES+).

EXAMPLE 16

2-[1-(3,4-Dichloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-3-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-dichloro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 3-picolylamine.

LC-MS (MeCN/H₂O: 1/1): R_(t)=3.29 min, 501 (M+1, ES+).

B Coupling of 1,2,3,4-Tetrahydroisoquinolines with 2-Bromoacetamides

B.1 Starting Materials: Synthesis of 1,2,3,4-TetrahydroisoquinolineDerivatives:

B.1.1 Synthesis of the Phenylethylamides:

Procedure I:

A solution of the respective phenylethylamine (80 mmol) and oftriethylamine (90 mmol) in THF (120 mL) was cooled to 0° C. and treatedportionwise with the respective acetyl chloride (80 mmol). Afterstirring for 10 min at 0° C. and for 14 h at room temperature a sat.aqueous NaHCO₃ solution was added, the phases were separated and theaqueous phase was extracted three times with ethyl acetate (150 mL). Thesolvent was removed in vacuo and the residue was either recrystalizedfrom toluene or purified by flash chromatography to give the followingamides:

N-[2-(3-Methoxy-phenyl)-ethyl]-3,4-dimethoxyphenyl-acetamide:

prepared by reaction of 3-methoxyphenylethylamine with3,4-dimethoxyphenyl acetyl chloride.

LC-MS: rt=4.1 min, 330 (M+1, ES+).

N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-phenyl-acetamide:

prepared by reaction of 3,4-dimethoxyphenylethylamine with phenyl acetylchloride.

N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-methoxyphenyl-acetamide:

prepared by reaction of 3,4-dimethoxyphenylethylamine with3-methoxyphenyl acetyl chloride.

LC-MS: rt=4.0 min, 330 (M+1, ES+).

N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-4-methoxyphenyl-acetamide:

prepared by reaction of 3,4-dimethoxyphenylethylamine with4-methoxyphenyl acetyl chloride.

LC-MS: rt=4.0 min, 330 (M+1, ES+).

N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-2,5-dimethoxyphenyl-acetamide:

prepared by reaction of 3,4-dimethoxyphenylethylamine with2,5-dimethoxyphenyl acetyl chloride.

LC-MS: rt=4.1 min, 360 (M+1, ES+).

N-[2-(2,5-Dimethoxy-phenyl)-ethyl]-3,4-dimethoxyphenyl-acetamide:

prepared by reaction of 2,5-dimethoxyphenylethylamine with3,4-dimethoxyphenyl acetyl chloride.

LC-MS: rt=4.2 min, 360 (M+1, ES+).

N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-phenyl-propionamide:

prepared by reaction of 3,4-dimethoxyphenylethylamine with 3-phenylpropionyl chloride.

LC-MS: rt=4.2 min, 314 (M+1, ES+).

N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-2-phenyl-butyramide:

prepared by reaction of 3,4-dimethoxyphenylethylamine with2-Phenylbutyryl chloride.

R_(f)=0.21 (ethyl acetate/heptane 1/1)

N-[2-(2,5-Dimethoxy-phenyl)-ethyl]-diphenyl-acetamide:

prepared by reaction of 2,5-dimethoxyphenylethylamine withdiphenylacetyl chloride.

LC-MS: rt=5.3 min, 376 (M+1, ES+).

N-[2-(2,5-Dimethoxy-phenyl)-ethyl]-2,5-dimethoxyphenyl-acetamide:

prepared by reaction of 2,5-dimethoxyphenylethylamine with2,5-dimethoxyphenyl acetyl chloride.

LC-MS: rt=4.6 min, 360 (M+1, ES+).

N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-4-chlorophenyl-acetamide:

prepared by reaction of 3,4-dimethoxyphenylethylamine with4-chlorophenyl acetyl chloride.

LC-MS: rt=4.4 min, 334 (M+1, ES+).

N-[2-(2,5-Dimethoxy-phenyl)-ethyl]-phenyl-acetamide:

prepared by reaction of 2,5-dimethoxyphenylethylamine with phenylacetylchloride.

LC-MS: rt=4.5 min, 300 (M+1, ES+).

N-[2(3-methoxy-isopropoxy-phenyl)-ethyl]-3,4-dimethoxyphenyl-acetamide:

prepared by reaction of 3-methoxy-4-isopropoxyphenylethylamine with3,4-dimethoxyphenyl acetyl chloride.

LC-MS: rt=4.2 min, 388 (M+1, ES+).

N-[2-3,4,5-Trimethoxy-phenyl)ethyl]-3,4-dimethoxyphenyl-acetamide:

prepared by reaction of 3,4,5-trimethoxyphenylethylamine with3,4-dimethoxyphenyl acetyl chloride.

LC-MS: rt=3.8 min, 390 (M+1, ES+).

N-[2-2,3,4-Trimethoxy-phenyl)-ethyl]-3,4-dimethoxyphenyl-acetamide:

prepared by reaction of 2,3,4-trimethoxyphenylethylamine with3,4-dimethoxyphenyl acetyl chloride.

LC-MS: rt=4.1 min, 390 (M+1, ES+).

N-[2-(3-Dimethoxy-phenyl)ethyl]-3,4-dimethoxyphenyl-acetamide:

prepared by reaction of 3,5-timethoxyphenylethylamine with3,4-dimethoxyphenyl acetyl chloride.

LC-MS: rt=4.2 min, 360 (M+1, ES+).

N-[2-3-Benzyloxy-4-methoxy-phenyethyl]-3,4-dimethoxyphenyl-acetamide:

prepared by reaction of 3-benzyloxy-4-methoxyphenylethylamine with3,4-dimethoxyphenyl acetyl chloride.

LC-MS: rt=4.7 min, 436 (M+1, ES+), 434 (M−1, ES−).

N-[2-(4-(Benzyloxy-3-methoxy-phenyl)ethyl]-3,4-dimethoxyphenyl-acetamide:

prepared by reaction of 4-benzyloxy-3-methoxyphenylethylamine with3,4-dimethoxyphenyl acetyl chloride.

LC-MS: rt=4.8 min, 436 (M+1, ES+).

N-[2-(2-Benzyloxy-5-methoxy-phenyl)ethyl]-3,4-dimethoxyphenyl-acetamide:

prepared by reaction of 2-benzyloxy-5-methoxyphenylethylamine with3,4-dimethoxyphenyl acetyl chloride.

LC-MS: rt=4.8 min, 436 (M+1, ES+).

N-[2-(5-Benzyloxy-2-methoxy-phenyl)-ethyl]-3,4-dimethoxyphenyl-acetamide:

prepared by reaction of 5-benzyloxy-2-methoxyphenylethylamine with3,4-dimethoxyphenyl acetyl chloride.

LC-MS: rt=4.9 min, 436 (M+1, ES+).

N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-benzyloxy-acetamide:

prepared by reaction of 3,4-dimethoxyphenylethylamine with benzyloxyacetyl chloride.

LC-MS: rt=4.2 min, 330 (M+1, ES+).

Procedure II:

A solution of the respective phenylethylamine (25.0 mmol) and therespective phenylacetic acid (25.0 mmol) in 100 mL toluene was refluxedfor 24 h in the presence of a Dean-Stark. The solvent was removed invacuo and the residue was either recrystalized from toluene or purifiedby flash chromatography to give the following amides:

N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3,4-methylenedioxyphenyl-acetamide:

prepared by reaction of 3,4-dimethoxyphenylethylamine and3,4-methylenedioxyphenylacetic acid.

LC-MS: rt=4.1 min, 344 (M+1, ES+).

N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-4-dimethylaminophenyl-acetamide:

prepared by reaction of 3,4-dimethoxyphenylethylamine and4-dimethyl-aminophenylacetic acid.

LC-MS: rt=3.1 min, 343 (M+1, ES+).

N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-4-fluorophenyl-acetamide:

prepared by reaction of 3,4-dimethoxyphenylethylamine and4-fluorophenyl-acetic acid.

LC-MS: rt=4.1 min, 318 (M+1, ES+).

N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3,4-difluorophenyl-acetamide:

prepared by reaction of 3,4-dimethoxyphenylethylamine and3,4-difluorophenylacetic acid.

LC-MS: rt=4.2 min, 336 (M+1, ES+).

N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3,4,5-trimethoxyphenyl-acetamide:

prepared by reaction of 3,4-dimethoxyphenylethylamine and3,4,5-trimethoxyphenylacetic acid.

LC-MS: rt=3.8 min, 390 (M+1, ES+).

N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-2,3,4-trimethoxyphenyl-acetamide:

prepared by reaction of 3,4-dimethoxyphenylethylamine and2,3,4-trimethoxyphenylacetic acid.

LC-MS: rt=4.1 min, 390 (M+1, ES+).

N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-naphthalen-2-yl-acetamide:

prepared by reaction of 3,4-dimethoxyphenylethylamine and2-naphthylacetic acid.

LC-MS: rt=4.9 min, 350 (M+1, ES+).

N-[2-2,5-Dimethoxy-phenyl)-ethyl]-3,4-methylenedioxyphenyl-acetamide:

prepared by reaction of 2,5-dimethoxyphenylethylamine and3,4-methylenedioxyphenylacetic acid.

LC-MS: rt=4.3 min, 344 (M+1, ES+).

N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-4-hydroxy-3-methoxy-phenyl-acetamide:

prepared by reaction of 3,4-dimethoxyphenylethylamine and4-hydroxy-3-methoxy-phenylacetic acid.

LC-MS: rt=3.6 min, 346 (M+1, ES+), 344 (M−1, ES−).

N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-benzyloxy-4-methoxy-phenyl-acetamide:

prepared by reaction of 3,4-dimethoxyphenylethylamine and3-benzyloxy-4-methoxy-phenylacetic acid.

LC-MS: rt=4.6 min, 436 (M+1, ES+), 434 (M−1, ES−).

B.1.2. Synthesis of 1,2,3,4-Tetrahydroisoquinolines viaBischler-Napieralski-Reaction (General Procedure):

To a suspension of the respective acetamide (60 mmol) in acetonitrile(100 mL) was added phosphorus oxychloride (16.2 mL, 177 mmol). Themixture was heated to reflux for 6 h and the solvent was removed invacuo. The resulting oil was taken up in MeOH (70 mL), evaporated todryness, dissolved in MeOH (130 mL) and cooled to 0° C. NaBH₄ was addedin small (!) portions and the reaction mixture was stirred for 14 h. Thesolvent was removed in vacuo, dichloromethane (150 mL) and water (100mL) were added, the phases were separated and the aqueous phase wasextracted three times with dichloromethane (100 mL). The combinedorganic phases were concentrated in vacuo to give the followingtetrahydroisoquinolines, which were purified either by flashchromatography or by crystallization as hydrochloride salt:

1-(3,4-Dimethoxy-benzyl)6-methoxy-1,2,3,4-tetrahydroisoquinoline:

prepared by cyclisation ofN-[2-(3-Methoxy-phenyl)-ethyl]-3,4-dimethoxyphenyl-acetamide.

LC-MS: rt=3.1 min, 314 (M+1, ES+).

1-Benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline:

prepared by cyclisation of N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-phenylacetamide.

R_(f) (dichloromethane/methanol 5/1)=0.51.

LC-MS: rt=3.1 min, 284 (M+1, ES+).

1-(3-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline:

prepared by cyclisation ofN-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-methoxyphenyl acetamide.

LC-MS: rt=3.0 min, 314 (M+1, ES+).

1-(4-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline:

prepared by cyclisation ofN-[2-(3,4-Dimethoxy-phenyl)-ethyl]-4-methoxyphenyl acetamide.

LC-MS: rt=3.0 min, 314 (M+1, ES+).

1-(2,5-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline:

prepared by cyclisation ofN-[2-(3,4-Dimethoxy-phenyl)-ethyl]-2,5-dimethoxy-phenyl acetamide.

LC-MS: rt=3.2 min, 344 (M+1, ES+).

1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline:

prepared by cyclisation ofN-[2-(2,5-Dimethoxy-phenyl)-ethyl]-3,4-dimethoxy-phenyl acetamide.

LC-MS: rt=3.3 min, 344 (M+1, ES+).

1-(2-Phenyl-ethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline:

prepared by cyclisation ofN-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-phenyl-propionamide.

LC-MS: rt=3.2 min, 298 (M+1, ES+).

1-(1-Phenyl-propyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline:prepared by cyclisation ofN-[2-(3,4-Dimethoxy-phenyl)-ethyl]-2-phenyl-butyramide.

LC-MS: rt=3.3 min 312 (M+1, ES+).

1-(Diphenylmethyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline:

prepared by cyclisation of N-[2-(2,5-Dimethoxy-phenyl)-ethyl]-diphenylacetamide.

LC-MS: rt=3.7 min, 360 (M+1, ES+).

1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline:

prepared by cyclisation ofN-[2-(2,5-Dimethoxy-phenyl)-ethyl]-2,5-dimethoxy-phenyl acetamide.

LC-MS: rt=3.6 min, 344 (M+1, ES+).

1-(4-Chloro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline:

prepared by cyclisation ofN-[2-(3,4-Dimethoxy-phenyl)-ethyl]-4-chloro-phenyl acetamide.

LC-MS: rt=3.2 min, 318 (M+1, ES+).

1-Benzyl-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline:

prepared by cyclisation of N-[2-(2,5-Dimethoxy-phenyl)-ethyl]-phenylacetamide.

LC-MS: rt=3.4 min, 284 (M+1, ES+).

1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydro-isoquinoline:

prepared by cyclisation ofN-[2-(3-Methoxy-4-isopropoxy-phenyl)-ethyl]-3,4-dimethoxy-phenylacetamide.

LC-MS: rt=3.32 min, 372 (M+1, ES+).

1-(3,4-Methylenedioxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline:

prepared by cyclisation ofN-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3,4-methylenedioxy-phenyl acetamide.

LC-MS: rt=3.0 min, 328 (M+1, ES+).

1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline;

prepared by cyclisation ofN-[2-(3,4-Dimethoxy-phenyl)-ethyl]-4-dimethyl-amino-phenyl acetamide.

LC-MS: rt=2.6 min, 327 (M+1, ES+).

1-(4-Fluoro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline:

prepared by cyclisation ofN-[2-(3,4-Dimethoxy-phenyl)-ethyl]-4-fluoro-phenyl acetamide.

LC-MS: rt=3.1 min, 302 (M+1, ES+).

1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline:

prepared by cyclisation ofN-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3,4-difluoro-phenyl acetamide.

LC-MS: rt=3.1 min. 320 (M+1, ES+).

1-(3,4,5-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline:

prepared by cyclisation ofN-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3,4,5-trimethoxy-phenyl acetamide.

LC-MS: rt=3.0 min, 374 (M+1, ES+).

1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydro-isoquinoline:

prepared by cyclisation ofN-[2-(3,4,5-Trimethoxy-phenyl)-ethyl]-3,4-dimethoxy-phenyl acetamide.

LC-MS: rt=3.2 min, 374 (M+1, ES+).

1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydro-isoquinoline:

prepared by cyclisation ofN-[2-(2,3,4-Trimethoxy-phenyl)-ethyl]-3,4-dimethoxy-phenyl acetamide.

LC-MS: rt=3.2 min, 374 (M+1, ES+).

1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline:

prepared by cyclisation ofN-[2-(3,5-Dimethoxy-phenyl)-ethyl]-3,4-dimethoxy-phenyl acetamide.

LC-MS: rt=3.5 min, 344 (M+1, ES+).

1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline:

prepared by cyclisation ofN-[2-(3,4-Dimethoxy-phenyl)-ethyl]-2,3,4-trimethoxy-phenyl acetamide.

LC-MS: rt=3.2 min, 374 (M+1, ES+).

1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline:

prepared by cyclisation ofN-[2-(3,4-Dimethoxy-phenyl)-ethyl]-naphthalen-2-yl acetamide.

LC-MS: rt=3.6 min, 334 (M+1, ES+).

1-(3,4-Methylenedioxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline:

prepared by cyclisation ofN-[2-(2,5-Dimethoxy-phenyl)-ethyl]-3,4-methylenedioxy-phenyl acetamide.

LC-MS: rt=3.2 min, 328 (M+1, ES+).

1-(3,4-Dimethoxy-benzyl)4-benzyloxy-7-methoxy-1,2,3,4-tetrahydro-isoquinoline:

prepared by cyclisation ofN-[2-(3-Benzyloxy-4-methoxy-phenyl)-ethyl]-3,4-dimethoxy-phenylacetamide.

LC-MS: rt=3.7 min, 420 (M+1, ES+).

1-(3,4-Dimethoxy-benzyl)-7-benzyloxy-6-methoxy-1,2,3,4-tetrahydro-isoquinoline:

prepared by cyclisation ofN-[2-(4-Benzyloxy-3-methoxy-phenyl)-ethyl]-3,4-dimethoxy-phenylacetamide.

LC-MS: rt=3.6 min, 420 (M+1, ES+).

1-(3,4-Dimethoxy-benzyl-5-benzyloxy-8-methoxy-1,2,3,4-tetrahydro-isoquinoline:

prepared by cyclisation ofN-[2-(2-Benzyloxy-5-methoxy-phenyl)-ethyl]-3,4-dimethoxy-phenylacetamide.

LC-MS: rt=4.1 min, 420 (M+1, ES+).

1-(3,4-Dimethoxy-benzyl)-8-benzyloxy-5-methoxy-1,2,3,4-tetrahydro-isoquinoline:

prepared by cyclisation ofN-[2-(5-Benzyloxy-2-methoxy-phenyl)-ethyl]-3,4-dimethoxy-phenylacetamide.

LC-MS: rt=3.9 min, 420 (M+1, ES+).

1-(4-Hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline:

prepared by cyclisation ofN-[2-(3,4-dimethoxy-phenyl)-ethyl]-4-hydroxy-3-methoxy-phenyl acetamide.

LC-MS: rt=2.8 min, 330 (M+1, ES+).

1-(3-Benzyloxy-4-methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline:

prepared by cyclisation ofN-[2-(3,4-dimethoxy-phenyl)-ethyl]-3-benzyloxy-4-methoxy-phenylacetamide.

LC-MS: rt=3.6 min, 420 (M+1, ES+).

1-Benzyloxymethyl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline:

prepared by cyclisation ofN-[2-(3,4-dimethoxy-phenyl)-ethyl]-benzyloxy-acetamide.

B.2. Alkylation of 1,2,3,4-Tetrahydroisoquinolines with2-Bromo-acetamides (General Procedure)

At −15° C. a solution of the respective amine in THF (250 μL, 0.40 M)was added to a solution of 2-bromoacetyl bromide in THF (500 μL, 0.20M). The reaction mixture was treated with a solution ofdiisopropylethylamine in THF (250 μL, 2.0 M), allowed to warm up to roomtemperature and stirred for 30 min. A solution of the respectivetetrahydroisoquinoline in DMSO (500 μL, 0.20 M) was added and themixture was heated to 75° C. for 18 h. After cooling to room temperaturewater (2.0 mL) and ethyl acetate (2.0 mL) were added, the phases wereseparated and the aqueous phase was extracted two times with ethylacetate. The combined organic phases were concentrated in vacuo to givethe following tetrahydroisoquinoline derivatives:

EXAMPLE 17

2-(1-Benzyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(2-methyl-benzyl)-acetamide:

prepared by reaction of 1-Benzyl-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 2-methylbenzylamine

LC-MS: rt=4.6 min, 385 (M+1, ES+).

EXAMPLE 18

2-(1-Benzyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(2-chloro-benzyl)-acetamide:

prepared by reaction of 1-Benzyl-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 2-chlorobenzylamine

LC-MS: rt=4.7 min, 405 (M+1, ES+).

EXAMPLE 19

2-(1-Benzyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-(1-naphthalen-1-yl-ethyl)-acetamide:

prepared by reaction of 1-Benzyl-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 1-naphthaleneethylamine

LC-MS: rt=4.7 and 4.8 min, 435 (M+1, ES+).

EXAMPLE 20

2-(1-Benzyl-3,4-dihydro-1H-isoquinolin-2-yl)-N-benzyl-N-methyl-acetamide:

prepared by reaction of 1-Benzyl-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with N-benzylmethylamine

LC-MS: rt=3.9 min, 385 (M+1, ES+).

EXAMPLE 21

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methoxy-benzyl)-acetamide:

prepared by reaction of1-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 2-methoxybenzylamine

LC-MS: rt=4.0 min, 491 (M+1, ES+).

EXAMPLE 22

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of1-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with benzylamine

LC-MS: rt=3.9 min, 461 (M+1, ES+).

EXAMPLE 23

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(4-methoxy-benzyl)-acetamide:

prepared by reaction of1-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 4-methoxybenzylamine

LC-MS: rt=3.9 min, 491 (M+1, ES+).

EXAMPLE 24

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(naphthalen-1-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 1-napthalenemethylamine

LC-MS: rt=4.3 min, 511 (M+1, ES+).

EXAMPLE 25

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(3-methyl-benzyl)-acetamide:

prepared by reaction of1-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 3-methylbenzylamine

LC-MS: rt=4.1 min, 475 (M+1, ES+).

EXAMPLE 26

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 1-amino-indane

LC-MS: rt=4.2 min, 487 (M+1, ES+).

EXAMPLE 27

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide:

prepared by reaction of1-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=4.3 min, 501 (M+1, ES+).

EXAMPLE 28

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-3-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-dimethoxy-benzyl)6-methoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 3-piconylamine

LC-MS: rt=3.1 min 462 (M+1, ES+).

EXAMPLE 29

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-4-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 4-piconylamine

LC-MS: rt=3.1 min, 462 (M+1, ES+).

EXAMPLE 30

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-fluoro-benzyl)-acetamide:

prepared by reaction of1-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 2-fluorobenzylamine

LC-MS: rt=4.0 min; 479 (M+1, ES+).

EXAMPLE 31

2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-benzyl-acetamide:

prepared by reaction of1-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetylbromide with benzylamine

LC-MS: rt=3.9 min, 431 (M+1, ES+).

EXAMPLE 32

2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(indan-1-yl)-acetamide:

prepared by reaction of1-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and 2-bromoacetylbromide with 1-amino-indane

LC-MS: rt=4.2 min, 457 (M+1, ES+).

EXAMPLE 33

2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-acetamide:

prepared by reaction of1-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and 2-bromoacetylbromide with 1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=4.3 min, 471 (M+1, ES+).

EXAMPLE 34

2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(pyridin-3-yl-methyl)-acetamide:

prepared by reaction of1-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetylbromide with 3-piconylamine

LC-MS: rt=3.0 min, 432 (M+1, ES+).

EXAMPLE 35

2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(2-methyl-benzyl)-acetamide:

prepared by reaction of1-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetylbromide with 2-methylbenzylamine

LC-MS: rt=4.1 min, 445 (M+1, ES+).

EXAMPLE 36

2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(2,5-difluoro-benzyl)-acetamide:

prepared by reaction of1-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetylbromide with 2,5-difluorobenzylamine

LC-MS: rt=4.1 min, 467 (M+1, ES+).

EXAMPLE 37

2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(4-fluoro-benzyl)-acetamide:

prepared by reaction of1-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetylbromide with 4-fluorobenzylamine

LC-MS: rt=4.0 min, 449 (M+1, ES+).

EXAMPLE 38

2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(2-chloro-benzyl)-acetamide:

prepared by reaction of1-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetylbromide with 2-chlorobenzylamine

LC-MS: rt=4.2 min, 465 (M+1, ES+).

EXAMPLE 39

2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(1-naphthalen-1-yl-ethyl)-acetamide:

prepared by reaction of1-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and 2-bromoacetylbromide with 1-naphthaleneethylamine

LC-MS: rt=4.3 and 4.4 min, 495 (M+1, ES+).

EXAMPLE 40

2-(1-Benzyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-benzyl-N-methyl-acetamide:

prepared by reaction of1-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetylbromide with N-benzylmethylamine

LC-MS: rt=3.8 min, 445 (M+1, ES+).

EXAMPLE 41

2-[1-(3-Methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methoxy-benzyl)-acetamide:

prepared by reaction of1-(3-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and2-bromoacetyl bromide with 2-methoxybenzylamine

LC-MS: rt=4.0 min, 491 (M+1, ES+).

EXAMPLE 42

2-[1-(3-Methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of1-(3-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and2-bromoacetyl bromide with benzylamine

LC-MS: rt=3.9 min, 461 (M+1, ES+).

EXAMPLE 43

2-[1-(3-Methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(naphthalen-1-yl-methyl)-acetamide:

prepared by reaction of1-(3-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and2-bromoacetyl bromide with naphthalen-1-yl-methylamine

LC-MS: rt=4.3 min, 511 (M+1, ES+).

EXAMPLE 44

2-[1-(3-Methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(3-methyl-benzyl)-acetamide:

prepared by reaction of1-(3-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and2-bromoacetyl bromide with 3-methyl-benzylamine

LC-MS: rt=4.1 min, 475 (M+1, ES+).

EXAMPLE 45

2-[1-(3-Methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of1-(3-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and2-bromoacetyl bromide with 1-Aminoindan

LC-MS: rt=4.2 min, 487 (M+1, ES+).

EXAMPLE 46

2-[1-(3-Methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-acetamide:

prepared by reaction of1-(3-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=4.3 min, 501 (M+1, ES+).

EXAMPLE 47

2-[1-(3-Methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-3-yl-methyl)-acetamide:

prepared by reaction of1-(3-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and2-bromoacetyl bromide with 3-aminomethyl-pyridine

LC-MS: rt=3.1 min, 462 (M+1, ES+).

EXAMPLE 48

2-[1-(3-Methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-fluoro-benzyl)-acetamide:

prepared by reaction of1-(3-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and2-bromoacetyl bromide with 2-fluoro-benzylamine

LC-MS: rt=4.0 min, 479 (M+1, ES+).

EXAMPLE 49

2-[1-(4-Methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of1-(4-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and2-bromoacetyl bromide with benzylamine

LC-MS: rt=3.9 min, 461 (M+1, ES+).

EXAMPLE 50

2-[1-(4-Methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(naphthalen-1-yl-methyl)-acetamide:

prepared by reaction of1-(4-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and2-bromoacetyl bromide with naphthalen-1-yl-methylamine

LC-MS: rt=4.2 min, 511 (M+1, ES+).

EXAMPLE 51

2-[1-(4-Methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of1-(4-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and2-bromoacetyl bromide with 1-Aminoindan

LC-MS: rt=4.1 min, 487 (M+1, ES+).

EXAMPLE 52

2-[1-(4-Methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-acetamide:

prepared by reaction of1-(4-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=4.2 min, 501 (M+1, ES+).

EXAMPLE 53

2-[1-(4-Methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-fluoro-benzyl)-acetamide:

prepared by reaction of1-(4-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and2-bromoacetyl bromide with 2-fluoro-benzylamine

LC-MS: rt=3.9 min, 479 (M+1, ES+).

EXAMPLE 54

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methoxy-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-methoxybenzylamine

LC-MS: rt=3.7 min, 521 (M+1, ES+).

EXAMPLE 55

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(4-methoxy-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 4-methoxybenzylamine

LC-MS: rt=3.7 min, 521 (M+1, ES+).

EXAMPLE 56

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(3-methyl-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 3-methylbenzylamine

LC-MS: rt=3.8 min, 505 (M+1, ES+).

EXAMPLE 57

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-indane

LC-MS: rt=3.9 min. 517 (M+1, ES+).

EXAMPLE 58

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(4-methyl-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 4-methylbenzylamine

LC-MS: rt=3.8 min, 505 (M+1, ES+).

EXAMPLE 59

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=4.0 min, 531 (M+1, ES+).

EXAMPLE 60

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-3-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 3-piconylamine

LC-MS: rt=2.9 min, 492 (M+1, ES+).

EXAMPLE 61

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-4-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 4-piconylamine

LC-MS: rt=2.9 min, 492 (M+1, ES+).

EXAMPLE 62

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-phenyl-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with aniline

LC-MS: rt=3.7 min, 477 (M+1, ES+).

EXAMPLE 63

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-fluoro-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-fluorobenzylamine

LC-MS: rt=3.7 min, 509 (M+1, ES+).

EXAMPLE 64

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[2-(4-methoxy-phenyl)-ethyl]-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 4-methoxyphenylethylamine

LC-MS: rt=3.8 min, 535 (M+1, ES+).

EXAMPLE 65

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methyl-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-methylbenzylamine

LC-MS: rt=3.9 min, 505 (M+1, ES+).

EXAMPLE 66

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-trifluoromethyl-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-trifluorobenzylamine

LC-MS: rt=4.0 min, 559 (M+1, ES+).

EXAMPLE 67

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2,5-difluoro-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2,5-difluorobenzylamine

LC-MS: rt=3.8 min, 527 (M+1, ES+).

EXAMPLE 68

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(4-fluoro-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 4-fluorobenzylamine

LC-MS: rt=3.8 min, 509 (M+1, ES+).

EXAMPLE 69

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-chloro-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-chlorobenzylamine

LC-MS: rt=3.9 min, 525 (M+1, ES+).

EXAMPLE 70

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2,4-dimethoxy-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2,4-dimethoxybenzylamine

LC-MS: rt=3.8 min, 551 (M+1, ES+).

EXAMPLE 71

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1-phenyl-ethyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-phenylethylamine

LC-MS: rt=3.7 min, 505 (M+1, ES+).

EXAMPLE 72

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1-naphthalen-1-yl-ethyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-naphthaleneethylamine

LC-MS: rt=4.0 min, 555 (M+1, ES+).

EXAMPLE 73

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-N-methyl-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with N-benzylmethylamine

LC-MS: rt=3.6 min. 505 (M+1, ES+).

EXAMPLE 74

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-furan-2-yl-methyl-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-aminomethylfurane

LC-MS: rt=3.5 min, 481 (M+1, ES+).

EXAMPLE 75

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-but-2-yl-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-butylamine

LC-MS: rt=0.57 min, 457 (M+1, ES+).

EXAMPLE 76

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-picolylamine

LC-MS: rt=0.46 min, 492 (M+1, ES+).

EXAMPLE 77

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(4-methoxy-indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-4-methoxy-indane

LC-MS: rt=0.71 min, 547 (M+1, ES+).

EXAMPLE 78

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(5,7-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with5,7-dimethyl-1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=0.80 min, 559 (M+1, ES+).

EXAMPLE 79

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with2-methyl-1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=0.76 min, 545 (M+1, ES+).

EXAMPLE 80

2-[1-(3,4-Dimethoxy-benzyl)6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(6-methoxy-indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-6-methoxy-indane

LC-MS: rt=0.72 min, 547 (M+1, ES+).

EXAMPLE 81

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(6-methyl-indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-6-methyl-indane

LC-MS: rt=0.74 min, 531 (M+1, ES+).

EXAMPLE 82

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(5-fluoro-indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-5-fluoro-indane

LC-MS: rt=0.72 min, 535 (M+1, ES+).

EXAMPLE 83

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(5-methoxy-indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-5-methoxy-indane

LC-MS: rt=0.75 min, 547 (M+1, ES+).

EXAMPLE 84

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(4-methyl-indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-4-methyl-indane

LC-MS: rt=0.86 min, 531 (M+1, ES+).

EXAMPLE 85

2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(3-methyl-indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-3-methyl-indane

LC-MS: rt=0.85 min, 531 (M+1, ES+).

EXAMPLE 86

2-[(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1S)-indan-1-yl]-acetamide:

prepared by reaction of(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1S)-1-amino-indane

LC-MS: rt=3.8 min, 517 (M+1, ES+).

EXAMPLE 87

2-[(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1R)-indan-1-yl]-acetamide:

prepared by reaction of(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1R)-1-amino-indane

LC-MS: rt=3.9 min, 517 (M+1, ES+).

EXAMPLE 88

2-[(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-acetamide:

prepared by reaction of(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=4.0 min, 531 (M+1, ES+).

EXAMPLE 89

2-[(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with benzylamine

LC-MS: rt=3.7 min, 491 (M+1, ES+).

EXAMPLE 90

2-[(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(naphthalen-1-yl-methyl)-acetamide:

prepared by reaction of(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with naphthalen-1-yl-methylamine

LC-MS: rt=4.0 min, 541 (M+1, ES+).

EXAMPLE 91

2-[(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methoxy-benzyl)-acetamide:

prepared by reaction of(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-methoxy-benzylamine

LC-MS: rt=3.7 min, 521 (M+1, ES+).

EXAMPLE 92

2-[(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-ethoxy-benzyl)-acetamide:

prepared by reaction of(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-ethoxy-benzylamine

LC-MS: rt=4.0 min, 535 (M+1, ES+).

EXAMPLE 93

2-[(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-N-methyl-acetamide:

prepared by reaction of(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with N-benzyl-N-methylamine

LC-MS: rt=3.7 min, 505 (M+1, ES+).

EXAMPLE 94

2-[(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1R,2S)-2-hydroxy-indan-1-yl]-acetamide:

prepared by reaction of(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol

LC-MS: rt=3.5 min, 533 (M+1, ES+).

EXAMPLE 95

2-[(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1S,2R)-2-hydroxy-indan-1-yl]-acetamide:

prepared by reaction of(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1S,2R)-1-amino-2-indanol

LC-MS: rt=3.5 min, 533 (M+1, ES+).

EXAMPLE 96

2-[(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-picolylamine

LC-MS: rt=3.1 min, 492 (M+1, ES+).

EXAMPLE 97

2-[(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-11-isoquinolin-2-yl]-N-(2-phenyl-ethyl)-acetamide:

prepared by reaction of(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-phenyl-ethylamine

LC-MS: rt=3.8 min, 505 (M+1, ES+).

EXAMPLE 98

2-[(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(cyclohexyl-methyl)-acetamide:

prepared by reaction of(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with cyclohexyl-methylamine

LC-MS: rt=4.0 min, 497 (M+1, ES+).

EXAMPLE 99

2-[1-(2,5-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(4-methoxy-benzyl)-acetamide:

prepared by reaction of1-(2,5-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 4-methoxybenzylamine

LC-MS: rt=3.9 min. 521 (M+1, ES+).

EXAMPLE 100

2-[1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methoxy-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-methoxybenzylamine

LC-MS: rt=4.3 min, 521 (M+1, ES+).

EXAMPLE 101

2-[1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4,-tetrahydroisoquinolineand 2-bromoacetyl bromide with benzylamine

LC-MS: rt=4.3 min, 491 (M+1, ES+).

EXAMPLE 102

2-[1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 3,4-dimethoxyphenylethylamine

LC-MS: rt=4.3 min, 565 (M+1, ES+).

EXAMPLE 103

2-[1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-indane

LC-MS: rt=4.5 min, 517 (M+1, ES+).

EXAMPLE 104

2-[1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-3-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 3-picolylamine

LC-MS: rt=3.4 min, 492 (M+1, ES+).

EXAMPLE 105

2-[1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1-isoquinolin-2-yl]-N-butyl-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with n-butylamine

LC-MS: rt=4.2 min, 457 (M+1, ES+).

EXAMPLE 106

2-[1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-fluoro-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-fluorobenzylamine

LC-MS: rt=4.4 min, 509 (M+1, ES+).

EXAMPLE 107

2-[1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-picolylamine

LC-MS: rt=3.7 min, 492 (M+1, ES+).

EXAMPLE 108

2-[1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[1,3,4]thiadiazol-2-yl-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-amino-1,3,4-thiadiazole

LC-MS: rt=3.8 min, 485 (M+1, ES+).

EXAMPLE 109

2-[1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1H-benzoimidazol-2-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-(aminomethyl)-benzimidazole

LC-MS: rt=3.4 min, 531 (M+1, ES+).

EXAMPLE 110

2-[1-(2-Phenyl-ethyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-3-yl-methyl)-acetamide:

prepared by reaction of1-(2-Phenyl-ethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 3-picolylamine

LC-MS: rt=2.7 min, 446 (M+1, ES+).

EXAMPLE 111

2-[1-(2-Phenyl-ethyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-fluoro-benzyl)-acetamide:

prepared by reaction of1-(2-Phenyl-ethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 2-fluorobenzylamine

LC-MS: rt=4.0 min, 463 (M+1, ES+).

EXAMPLE 112

2-[1-(2-Phenyl-ethyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-cyclohexyl-acetamide:

prepared by reaction of1-(2-Phenyl-ethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with cyclohexylamine

LC-MS: rt=4.0 min, 437 (M+1, ES+).

EXAMPLE 113

2-[1-(1-Phenyl-propyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of1-(1-Phenyl-propyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with benzylamine

LC-MS: rt=4.4 min, 459 (M+1, ES+).

EXAMPLE 114

2-[1-(1-Phenyl-propyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of1-(1-Phenyl-propyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 2-picolylamine

LC-MS: rt=3.7 min, 460 (M+1, ES+).

EXAMPLE 115

2-[1-(Diphenyl-methyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methoxy-benzyl)-acetamide:

prepared by reaction of1-(Diphenyl-methyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 2-methoxy-benzylamine

LC-MS: rt=5.2 min, 537 (M+1, ES+).

EXAMPLE 116

2-[1-(Diphenyl-methyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of1-(Diphenyl-methyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 2-picolylamine

LC-MS: rt=4.3 min, 508 (M+1, ES+).

EXAMPLE 117

2-[1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-indane

LC-MS: rt=4.6 min, 517 (M+1, ES+).

EXAMPLE 118

2-[1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with benzylamine

LC-MS: rt=4.4 min, 491 (M+1, ES+).

EXAMPLE 119

2-[1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methoxy-benzyl)-acetamide:

prepared by reaction of1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-methoxy-benzyl-amine

LC-MS: rt=4.5 min, 521 (M+1, ES+).

EXAMPLE 120

2-[1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-ethoxy-benzyl)-acetamide:

prepared by reaction of1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-ethoxy-benzyl-amine

LC-MS: rt=4.6 min, 535 (M+1, ES+).

EXAMPLE 121

2-[1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1R,2S)-2-hydroxy-indan-1-yl]-acetamide:

prepared by reaction of1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol

LC-MS: rt=4.1 min, 533 (M+1, ES+).

EXAMPLE 122

2-[1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1S,2R)-2-hydroxy-indan-1-yl]-acetamide:

prepared by reaction of1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1S,2R)-1-amino-2-indanol

LC-MS: rt=4.1 min, 533 (M+1, ES+).

EXAMPLE 123

2-[1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-picolylamine

LC-MS: rt=3.8 min, 492 (M+1, ES+).

EXAMPLE 124

2-[1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-2-yl)-acetamide:

prepared by reaction of1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-amino-indane

LC-MS: rt=4.6 min, 517 (M+1, ES+).

EXAMPLE 125

2-[1-(4-Chloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of1-(4-Chloro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 1-amino-indane

LC-MS: rt=4.8 min, 491 (M+1, ES+).

EXAMPLE 126

2-[1-(4-Chloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of1-(4-Chloro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with benzylamine

LC-MS: rt=4.4 min. 465 (M+1, ES+).

EXAMPLE 127

2-[1-(4-Chloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-ethoxy-benzyl)-acetamide:

prepared by reaction of1-(4-Chloro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 2-ethoxy-benzylamine

LC-MS: rt=4.7 min, 509 (M+1, ES+).

EXAMPLE 128

2-[1-(4-Chloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1R,2S)-2-hydroxy-indan-1-yl]-acetamide:

prepared by reaction of1-(4-Chloro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol

LC-MS: rt=4.0 min, 507 (M+1, ES+), 505 (M−1, ES−).

EXAMPLE 129

2-[1-(4-Chloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of1-(4-Chloro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 2-picolylamine

LC-MS: rt=3.6 min, 466 (M+1, ES+).

EXAMPLE 130

2-[1-(4-Chloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-2-yl)-acetamide:

prepared by reaction of1-(4-Chloro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 2-amino-indane

LC-MS: rt=4.5 min, 491 (M+1, ES+).

EXAMPLE 131

2-(1-Benzyl-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-[(1S,2R)-2-hydroxy-indan-1-yl)-acetamide:

prepared by reaction of1-Benzyl-5,8-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and 2-bromoacetylbromide with (1S,2R)-1-amino-2-indanol

LC-MS: rt=4.2 min, 473 (M+1, ES+).

EXAMPLE 132

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1S)-indan-1-yl]-acetamide:

prepared by reaction of1-3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1S)-1-amino-indane

LC-MS: rt=4.1 min, 545 (M+1, ES+).

EXAMPLE 133

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=4.3 min, 559 (M+1, ES+).

EXAMPLE 134

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with benzylamine

LC-MS: rt=3.9 min, 519 (M+1, ES+).

EXAMPLE 135

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(naphthalen-1-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with naphthalen-1-yl-methylamine

LC-MS: rt=4.3 min, 569 (M+1, ES+).

EXAMPLE 136

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methoxy-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-methoxy-benzylamine

LC-MS: rt=4.0 min, 549 (M+1, ES+).

EXAMPLE 137

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-ethoxy-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-ethoxy-benzylamine

LC-MS: rt=4.2 min, 563 (M+1, ES+).

EXAMPLE 138

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1R)-indan-1-yl]-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1R)-1-amino-indane

LC-MS: rt=4.1 min, 545 (M+1, ES+).

EXAMPLE 139

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-N-methyl-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with N-benzyl-N-methyl-amine

LC-MS: rt=3.9 min, 533 (M+1, ES+).

EXAMPLE 140

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1,2,3,4-tetrahydronaphthalen-1-y)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=4.0 min, 545 (M+1, ES+).

EXAMPLE 141

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-picolylamine

LC-MS: rt=3.4 min, 520 (M+1, ES+).

EXAMPLE 142

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1S,2R)-2-hydroxy-indan-1-yl]-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1S,2R)-1-amino-2-indanol

LC-MS: rt=3.8 min, 561 (M+1, ES+).

EXAMPLE 143

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-phenyl-ethyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-phenyl-ethylamine

LC-MS: rt=4.0 min, 533 (M+1, ES+).

EXAMPLE 144

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-cyclohexyl-methyl-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with cyclohexyl-methylamine

LC-MS: rt=4.2 min, 525 (M+1, ES+).

EXAMPLE 145

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with5,7-dimethyl-1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=0.84 min, 587 (M+1, ES+).

EXAMPLE 146

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with2-methyl-1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=0.81 min, 573 (M+1, ES+).

EXAMPLE 147

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(4-methyl-indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-4-methyl-indane

LC-MS: rt=0.79 min, 559 (M+1, ES+).

EXAMPLE 148

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(4-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with4-methyl-1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=0.81 min, 573 (M+1, ES+).

EXAMPLE 149

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(6-methoxy-indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-6-methoxy-indane

LC-MS: rt=0.77 min, 575 (M+1, ES+).

EXAMPLE 150

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(6-methyl-indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-6-methyl-indane

LC-MS: rt=0.80 min. 559 (M+1, ES+).

EXAMPLE 151

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(5-fluoro-indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-5-fluoro-indane

LC-MS: rt=0.78 min, 563 (M+1, ES+).

EXAMPLE 152

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methyl-indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-2-methyl-indane

LC-MS: rt=0.79 min, 559 (M+1, ES+).

EXAMPLE 153

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(3-methyl-indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-3-methyl-indane

LC-MS: rt=0.79 min, 559 (M+1, ES+).

EXAMPLE 154

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(3-phenyl-indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-3-phenyl-indane

LC-MS: rt=0.86 min, 621 (M+1, ES+).

EXAMPLE 155

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(5,6-dimethoxy-indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-5,6-dimethoxy-indane

LC-MS: rt=0.72 min, 605 (M+1, ES+).

EXAMPLE 156

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(5-methoxy-indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-5-methoxy-indane

LC-MS: rt=0.76 min, 575 (M+1, ES+).

EXAMPLE 157

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(5-bromo-indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-5-bromo-indane

LC-MS: rt=0.82 min, 623 (M+1, ES+).

EXAMPLE 158

2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylamine

LC-MS: rt=0.81 min, 573 (M+1, ES+).

EXAMPLE 159

2-[1-(3,4-Methylenedioxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Methylenedioxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-indane

LC-MS: rt=4.2 min, 501 (M+1, ES+).

EXAMPLE 160

2-[1-(3,4-Methylenedioxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of1-(3,4-Methylenedioxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with benzylamine

LC-MS: rt=4.0 min, 475 (M+1, ES+).

EXAMPLE 161

2-[1-(3,4-Methylenedioxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-ethoxy-benzyl)-acetamide:

prepared by reaction of1-(3,4-Methylenedioxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-ethoxy-benzylamine

LC-MS: rt=4.2 min, 519 (M+1, ES+).

EXAMPLE 162

2-[1-(3,4-Methylenedioxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1R,2S)-2-hydroxy-indan-1-yl]-acetamide:

prepared by reaction of1-(3,4-Methylenedioxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol

LC-MS: rt=3.7 min, 517 (M+1, ES+), 515 (M−1, ES−).

EXAMPLE 163

2-[1-(3,4-Methylenedioxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-2-yl)-acetamide:

prepared by reaction of1-(3,4-Methylenedioxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-amino-indane

LC-MS: rt=4.1 min, 501 (M+1, ES+).

EXAMPLE 164

2-[1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-indane

LC-MS: rt=3.7 min, 500 (M+1, ES+).

EXAMPLE 165

2-[1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide:

prepared by reaction of1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=3.9 min, 514 (M+1, ES+).

EXAMPLE 166

2-[1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with benzylamine

LC-MS: rt=3.5 min, 474 (M+1, ES+).

EXAMPLE 167

2-[1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(naphthalen-1-yl-methyl)-acetamide:

prepared by reaction of1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with naphthalen-1-yl-methylamine

LC-MS: rt=4.0 min, 524 (M+1, ES+).

EXAMPLE 168

2-[1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methoxy-benzyl)-acetamide:

prepared by reaction of1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-methoxy-benzylamine

LC-MS: rt=3.6 min, 504 (M+1, ES+).

EXAMPLE 169

2-[1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-ethoxy-benzyl)-acetamide:

prepared by reaction of1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-ethoxy-benzylamine

LC-MS: rt=3.8 min, 518 (M+1, ES+).

EXAMPLE 170

2-[1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1R,2S)-2-hydroxy-indan-1-yl]-acetamide:

prepared by reaction of1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol

LC-MS: rt=3.3 min, 516 (M+1, ES+).

EXAMPLE 171

2-[1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-3,4-dihydro-11H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of1-(4-Dimethylamino-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-picolylamine

LC-MS: rt=2.9 min, 475 (M+1, ES+).

EXAMPLE 172

2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of1-(4-Fluoro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 1-amino-indane

LC-MS: rt=4.3 min, 475 (M+1, ES+).

EXAMPLE 173

2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide:

prepared by reaction of1-(4-Fluoro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=4.5 min, 489 (M+1, ES+).

EXAMPLE 174

2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-ethoxy-benzyl)-acetamide:

prepared by reaction of1-(4-Fluoro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 2-ethoxy-benzylamine

LC-MS: rt=4.3 min, 493 (M+1, ES+).

EXAMPLE 175

2-[1-(4-Fluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-N-methyl-acetamide:

prepared by reaction of1-(4-Fluoro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with N-benzyl-N-methylamine

LC-MS: rt=3.8 min, 463 (M+1, ES+).

EXAMPLE 176

2-[1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-N-methyl-acetamide:

prepared by reaction of1-(3,4-Difluoro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with N-benzyl-N-methylamine

LC-MS: rt=3.9 min, 481 (M+1, ES+).

EXAMPLE 177

2-[1-(3,4,5-Trimethoxy-benzyl)6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of1-(3,4,5-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-indane

LC-MS: rt=4.0 min, 547 (M+1, ES+).

EXAMPLE 178

2-[1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-indane

LC-MS: rt=4.5 min, 547 (M+1, ES+).

EXAMPLE 179

2-[1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=4.7 min, 561 (M+1, ES+).

EXAMPLE 180

2-[1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with benzylamine

LC-MS: rt=4.4 min, 521 (M+1, ES+).

EXAMPLE 181

2-[1-(3,4-Dimethoxy-benzyl)6,7,8-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(naphthalen-1-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with naphthalen-1-yl-methylamine

LC-MS: rt=4.8 min, 571 (M+1, ES+).

EXAMPLE 182

2-[1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methoxy-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-methoxy-benzyl-amine

LC-MS: rt=4.4 min, 551 (M+1, ES+).

EXAMPLE 183

2-[1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-ethoxy-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-ethoxy-benzyl-amine

LC-MS: rt=4.6 min, 565 (M+1, ES+).

EXAMPLE 184

2-[1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-N-methyl-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with N-benzyl-N-methylamine

LC-MS: rt=4.0 min, 535 (M+1, ES+).

EXAMPLE 185

2-[1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1S,2R)-2-hydroxy-indan-1-yl]-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1S,2R)-1-amino-2-indanol

LC-MS: rt=4.0 min, 563 (M+1, ES+), 561 (M−1, ES−).

EXAMPLE 186

2-[1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1R,2S)-2-hydroxy-indan-1-yl]-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol

LC-MS: rt=4.0 min, 563 (M+1, ES+).

EXAMPLE 187

2-[1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-picolylamine

LC-MS: rt=3.7 min, 522 (M+1, ES+).

EXAMPLE 188

2-[1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-phenyl-ethyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-phenyl-ethylamine

LC-MS: rt=4.5 min, 535 (M+1, ES+).

EXAMPLE 189

2-[1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(cyclohexyl-methyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with cyclohexyl-methylamine

LC-MS: rt=4.6 min, 527 (M+1, ES+).

EXAMPLE 190

2-[1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-indane

LC-MS: rt=4.3 min. 547 (M+1, ES+).

EXAMPLE 191

2-[1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=4.4 min, 561 (M+1, ES+).

EXAMPLE 192

2-[1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with benzylamine

LC-MS: rt=4.1 min, 521 (M+1, ES+).

EXAMPLE 193

2-[1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(naphthalen-1-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with naphthalen-1-yl-methylamine

LC-MS: rt=4.5 min, 571 (M+1, ES+).

EXAMPLE 194

2-[1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methoxy-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-methoxy-benzyl-amine

LC-MS: rt=4.2 min, 551 (M+1, ES+).

EXAMPLE 195

2-[1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-ethoxy-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-ethoxy-benzyl-amine

LC-MS: rt=4.3 min. 565 (M+1, ES+).

EXAMPLE 196

2-[1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-N-methyl-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with N-benzyl-N-methyl-amine

LC-MS: rt=3.9 min, 535 (M+1, ES+).

EXAMPLE 197

2-[1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1R,2S)-2-hydroxy-indan-1-yl]-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol

LC-MS: rt=3.8 min, 563 (M+1, ES+), 561 (M−1, ES−).

EXAMPLE 198

2-[1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1S,2R)-2-hydroxy-indan-1-yl]-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1S,2R)-1-amino-2-indanol

LC-MS: rt=3.8 min, 563 (M+1, ES+), 561 (M−1, ES−).

EXAMPLE 199

2-[1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-picolylamine

LC-MS: rt=3.4 min, 522 (M+1, ES+).

EXAMPLE 200

2-[1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-phenyl-ethyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-phenyl-ethylamine

LC-MS: rt=4.2 min, 535 (M+1, ES+).

EXAMPLE 201

2-[1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(cyclohexyl-methyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with cyclohexyl-methylamine

LC-MS: rt=4.3 min, 527 (M+1, ES+).

EXAMPLE 202

2-[l-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-2-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-amino-indane

LC-MS: rt=4.2 min, 547 (M+1, ES+).

EXAMPLE 203

2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1S)-indan-1-yl]-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1S)-1-amino-indane

LC-MS: rt=4.4 min, 517 (M+1, ES+).

EXAMPLE 204

2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1R)-indan-1-yl]-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1R)-1-amino-indane

LC-MS: rt=4.4 min, 517 (M+1, ES+).

EXAMPLE 205

2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=4.5 min, 531 (M+1, ES+).

EXAMPLE 206

2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with benzylamine

LC-MS: rt=4.2 min, 491 (M+1, ES+).

EXAMPLE 207

2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(naphthalen-1-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with naphthalen-1-yl-methylamine

LC-MS: rt=4.5 min, 541 (M+1, ES+).

EXAMPLE 208

2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methoxy-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-methoxy-benzyl-amine

LC-MS: rt=4.2 min, 521 (M+1, ES+).

EXAMPLE 209

2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-ethoxy-benzyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-ethoxy-benzyl-amine

LC-MS: rt=4.4 min, 535 (M+1, ES+).

EXAMPLE 210

2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-picolylamine

LC-MS: rt=4.2 min, 492 (M+1, ES+).

EXAMPLE 211

2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1R,2S)-2-hydroxy-indan-1-yl]-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol

LC-MS: rt=3.9 min, 533 (M+1, ES+).

EXAMPLE 212

2-[1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1S,2R)-2-hydroxy-indan-1-yl]-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1S,2R)-1-amino-2-indanol

LC-MS: rt=3.9 min, 533 (M+1, ES+).

EXAMPLE 213

2-[1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-indane

LC-MS: rt=4.1 min, 547 (M+1, ES+).

EXAMPLE 214

2-[1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide:

prepared by reaction of1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=4.3 min, 561 (M+1, ES+).

EXAMPLE 215

2-[1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with benzylamine

LC-MS: rt=3.9 min, 521 (M+1, ES+).

EXAMPLE 216

2-[1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(naphthalen-1-yl-methyl)-acetamide:

prepared by reaction of1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with naphthalen-1-yl-methylamine

LC-MS: rt=4.3 min, 571 (M+1, ES+).

EXAMPLE 217

2-[1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methoxy-benzyl)-acetamide:

prepared by reaction of1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-methoxy-benzyl-amine

LC-MS: rt=4.0 min, 551 (M+1, ES+).

EXAMPLE 218

2-[1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-ethoxy-benzyl)-acetamide:

prepared by reaction of1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-ethoxy-benzyl-amine

LC-MS: rt=4.1 min, 565 (M+1, ES+).

EXAMPLE 219

2-[1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1R,2S)-2-hydroxy-indan-1-yl)-acetamide:

prepared by reaction of1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol

LC-MS: rt=3.7 min, 563 (M+1, ES+), 561 (M−1, ES−).

EXAMPLE 220

2-[1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-phenyl-ethyl)-acetamide:

prepared by reaction of1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-phenyl-ethylamine

LC-MS: rt=4.0 min, 535 (M+1, ES+).

EXAMPLE 221

2-[1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-2-yl)-acetamide:

prepared by reaction of1-(2,3,4-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-ammo-indane

LC-MS: rt=4.1 min, 547 (M+1, ES+).

EXAMPLE 222

2-[1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-indane

LC-MS: rt=4.8 min, 507 (M+1, ES+).

EXAMPLE 223

2-[1-Naphthalen-2-yl-methyl)-6,7-dimethoxy-3,4-dihydro-11H-isoquinolin-2-yl]-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide:

prepared by reaction of1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=4.9 min, 521 (M+1, ES+).

EXAMPLE 224

2-[1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with benzylamine

LC-MS: rt=4.5 min, 481 (M+1, ES+).

EXAMPLE 225

2-[1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(naphthalen-1-yl-methyl)-acetamide:

prepared by reaction of1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with naphthalen-1-yl-methylamine

LC-MS: rt=4.8 min, 531 (M+1, ES+).

EXAMPLE 226

2-[1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methoxy-benzyl)-acetamide:

prepared by reaction of1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-methoxy-benzyl-amine

LC-MS: rt=4.5 min, 511 (M+1, ES+).

EXAMPLE 227

2-[1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-ethoxy-benzyl)-acetamide:

prepared by reaction of1-Naphthalen-2-yl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-ethoxy-benzyl-amine

LC-MS: rt=4.7 min, 525 (M+1, ES+).

EXAMPLE 228

2-[1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-N-methyl-acetamide:

prepared by reaction of1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with N-benzyl-N-methyl-amine

LC-MS: rt=4.2 min. 495 (M+1, ES+).

EXAMPLE 229

1-(3,4-Dihydro-1H-isoquinolin-2-yl)-2-[1-Naphthalen-2-yl-methyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-ethanone:

prepared by reaction of1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1,2,3,4-tetrahydroisoquinoline

LC-MS: rt=4.3 min, 507 (M+1, ES+).

EXAMPLE 230

2-[1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-picolylamine

LC-MS: rt=4.4 min, 482 (M+1, ES+).

EXAMPLE 231

2-[1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1R,2S)-2-hydroxy-indan-1-yl]-acetamide:

prepared by reaction of1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol

LC-MS: rt=4.1 min, 523 (M+1, ES+), 521 (M−1, ES−).

EXAMPLE 232

2-[1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1S,2R)-2-hydroxy-indan-1-yl]-acetamide:

prepared by reaction of1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1S,2R)-1-amino-2-indanol

LC-MS: rt=4.1 min, 523 (M+1, ES+), 521 (M−1, ES−).

EXAMPLE 233

2-[1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-2-yl)-acetamide:

prepared by reaction of1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-amino-indane

LC-MS: rt=4.7 min, 507 (M+1, ES+).

EXAMPLE 234

2-[1-(3-Bromo-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide:

prepared by reaction of1-(3-Bromo-4-methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine

LC-MS: rt=4.7 min, 579 (M+1, ES+).

EXAMPLE 235

2-[1-(3-Bromo-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of1-(3-Bromo-4-methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-indane

LC-MS: rt=4.5 min, 565 (M+1, ES+).

EXAMPLE 236

2-[1-(3-Bromo-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of1-(3-Bromo-4-methoxy-benzyl)6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with benzylamine

LC-MS: rt=4.3 min, 539 (M+1, ES+).

EXAMPLE 237

2-[1-(3-Bromo-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(naphthalen-1-yl-methyl)-acetamide:

prepared by reaction of1-(3-Bromo-4-methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with naphthalen-1-yl-methylamine

LC-MS: rt=4.7 min, 589 (M+1, ES+).

EXAMPLE 238

2-[1-(3-Bromo-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-ethoxy-benzyl)-acetamide:

prepared by reaction of1-(3-Bromo-4-methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-ethoxy-benzylamine

LC-MS: rt=4.6 min, 583 (M+1, ES+).

EXAMPLE 239

2-[1-(3-Bromo-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of1-(3-Bromo-4-methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-picolylamine

LC-MS: rt=3.6 min, 541 (M+1, ES+).

EXAMPLE 240

2-[1-(3-Bromo-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1R,2S)-2-hydroxy-indan-1-yl]-acetamide:

prepared by reaction of1-(3-Bromo-4-methoxy-benzyl)-6,7-methoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol

LC-MS: rt=4.0 min 581 (M+1, ES+), 579 (M−1, ES−).

EXAMPLE 241

2-[1-(3,4-Methylenedioxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-Methylenedioxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-picolylamine

LC-MS: rt=3.8 min, 476 (M+1, ES+).

EXAMPLE 242

2-[1-(3,4-Methylenedioxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methoxy-benzyl)-acetamide:

prepared by reaction of1-(3,4-Methylenedioxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-methoxy-benzylamine

LC-MS: rt=4.6 min, 505 (M+1, ES+).

EXAMPLE 243

2-[1-(3,4-Methylenedioxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[1,3,4]thiadiazol-2-yl-acetamide:

prepared by reaction of1-(3,4-Methylenedioxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-amino-1,3,4-thiadiazole

LC-MS: rt=4.4 min, 469 (M+1, ES+).

EXAMPLE 244

2-[1-(3,4-Methylenedioxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1H-benzoimidazol-2-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-Methylenedioxy-benzyl)5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-(aminomethyl)-benzimidazole

LC-MS: rt=3.8 min, 515 (M+1, ES+).

EXAMPLE 245

2-[1-(3,4-Methylenedioxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1H-indazol-6-yl)-acetamide:

prepared by reaction of1-(3,4-Methylenedioxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 6-aminoindazole

LC-MS: rt=4.4 min, 501 (M+1, ES+).

Analogous to the above mentioned procedure, but in larger scale, thefollowing tetrahydroisoquinoline derivatives were synthesized:

EXAMPLE 246

2-[1-(3,4-Dimethoxy-benzyl)-6-benzyloxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with benzylamine

LC-MS: rt=4.5 min, 567 (M+1, ES+).

EXAMPLE 247

2-[1-(3,4-Dimethoxy-benzyl)-7-benzyloxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-7-benzyloxy-6-methoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with benzylamine

LC-MS: rt=4.4 min, 567 (M+1, ES+).

2-[1-(3,4-Dimethoxy-benzyl)-7-benzyloxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-7-benzyloxy-6-methoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 1-amino-indane

LC-MS: rt=4.5 min, 593 (M+1, ES+).

EXAMPLE 248

2-[1-(3,4-Dimethoxy-benzyl)-5-benzyloxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-5-benzyloxy-8-methoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-picolylamine

LC-MS: rt=4.4 min, 568 (M+1, ES+).

2-[1-(3,4-Dimethoxy-benzyl)-8-benzyloxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of1-(3,4-Dimethoxy-benzyl)-8-benzyloxy-5-methoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with 2-picolylamine

LC-MS: rt=4.4 min, 568 (M+1, ES+).

EXAMPLE 249

2-[1-(4-Hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of1-(4-Hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with benzylamine

LC-MS: rt=3.4 min, 477 (M+1, ES+).

2-[1-(3-Benzyloxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of1-(3-Benzyloxy-4-methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineand 2-bromoacetyl bromide with benzylamine

LC-MS: rt=4.4 min, 567 (M+1, ES+).

2-(1-Benzyloxymethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(indan-1-yl)-acetamide:

prepared by reaction of1-Benzyloxymethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and2-bromoacetyl bromide with 1-amino-indane

LC-MS: rt=4.3 min, 487 (M+1, ES+).

C Coupling of Phenols with Alkylbromides, Heteroarylchlorides,Heteroaryl-methyl-sulfones and Carbamoylchlorides

C.1 Starting Materials: Deprotection of Benzylic Ethers:

To a mixture of MeOH (60 mL) and formic acid (11.0 mL) was addedPalladium (10% Pd/C, wet, 274 mg). The respective benzylic ether (4.0mmol) was added portionwise and the mixture was stirred for 40 h. Duringthis period further portions of Pd/C were added until the startingmaterial was consumed. The mixture was filtered, the solvent was removedin vacuo and the residue was purified by flash-chromatography to givethe following phenols:

EXAMPLE 250

2-[1-(3,4-dimethoxy-benzyl)-6-hydroxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by deprotection of2-[1-(3,4-dimethoxy-benzyl)-6-benzyloxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide

LC-MS: rt=3.5 min, 477 (M+1, ES+).

EXAMPLE 251

2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by deprotection of2-[1-(3,4-dimethoxy-benzyl)-7-benzyloxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide

LC-MS: rt=3.5 min, 477 (M+1, ES+).

EXAMPLE 252

2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by deprotection of2-[1-(3,4-dimethoxy-benzyl)-7-benzyloxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide

LC-MS: rt=3.7 min, 503 (M+1, ES+), 501 (M−1, ES−).

2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by deprotection of2-[1-(3,4-dimethoxy-benzyl)-5-benzyloxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide

LC-MS: rt=3.2 min, 478 (M+1, ES+), 476 (M−1, ES−).

2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by deprotection of2-[1-(3,4-dimethoxy-benzyl)-8-benzyloxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide

LC-MS: rt=3.3 min, 478 (M+1, ES+), 476 (M−1, ES−).

EXAMPLE 253

2-[1-(3-Hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by deprotection of2-[1-(3-Benzyloxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

LC-MS: rt=3.5 min, 477 (M+1, ES+), 475 (M−1, ES−).

2-(1-Hydroxymethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(indan-1-yl)-acetamide:

prepared by deprotection of2-(1-Benzyloxymethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(indan-1-yl)-acetamide:

LC-MS: rt=3.1 min, 397 (M+1, ES+).

C.2 Alkylation of Phenols with Alkylbromides (General Procedure):

At RT a solution of the respective phenol in DMF (250 μL, 0.40 M) wasadded to K₂CO₃ (70 mg). The reaction mixture was treated with a solutionof the respective alkyl bromide in DMF (150 μL, 1.00 M, shaken at 100°C. for 90 min and cooled to RT. After addition of another portion ofalkyl bromide (150 μL, 1.00 M), shaking (100° C., 90 min) and cooling toRT a solution of triethylamine in THF (250 μL, 2.0 M) was added and themixture was shaken for 14 h. Water (2.0 mL) and ethyl acetate (2.0 mL)were added, the phases were separated and the aqueous phase wasextracted two times with ethyl acetate. The combined organic phases wereconcentrated in vacuo to give the following tetrahydroisoquinolinederivatives:

EXAMPLE 254

2-[1-(3,4-dimethoxy-benzyl)-6-ethoxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-6-hydroxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith ethyl iodide

LC-MS: rt=3.8 min, 505 (M+1, ES+).

EXAMPLE 255

2-[1-(3,4-dimethoxy-benzyl)-6-propoxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-6-hydroxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith propyl bromide

LC-MS: rt=4.1 min, 519 (M+1, ES+).

EXAMPLE 256

2-[1-(3,4-dimethoxy-benzyl)-6-allyloxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[l-(3,4-dimethoxy-benzyl)-6-hydroxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith allyl bromide

LC-MS: rt=4.0 min, 517 (M+1, ES+).

EXAMPLE 257

2-[1-(3,4-dimethoxy-benzyl)-6-(cyclopropyl-methoxy)-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-6-hydroxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith cyclopropylmethyl bromide

LC-MS: rt=4.1 min, 531 (M+1, ES+).

EXAMPLE 258

[2-(Benzylcarbamoyl-methyl)-1-(3,4-dimethoxy-benzyl)-7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-aceticacid ethyl ester:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-6-hydroxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith ethyl bromoacetate

EXAMPLE 259

2-[1-(3,4-dimethoxy-benzyl)-6-(3-fluoro-propoxy)-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-6-hydroxy-7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith 1-bromo-3-fluoro-propane

LC-MS: rt=4.0 min, 537 (M+1, ES+).

EXAMPLE 260

2-[1-(3,4-dimethoxy-benzyl)-7-ethoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith ethyl iodide

LC-MS: rt=3.8 min, 505 (M+1, ES+).

EXAMPLE 261

2-[1-(3,4-dimethoxy-benzyl)-7-propoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith propyl bromide

LC-MS: rt=4.0 min, 519 (M+1, ES+).

EXAMPLE 262

2-[1-(3,4-dimethoxy-benzyl)-7-butoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith butyl bromide

LC-MS: rt=4.2 min, 533 (M+1, ES+).

EXAMPLE 263

2-[1-(3,4-dimethoxy-benzyl)-7-allyloxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith allyl bromide

LC-MS: rt=3.9 min, 517 (M+1, ES+).

EXAMPLE 264

2-[1-(3,4-dimethoxy-benzyl)-7-(cyclopropyl-methoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith cyclopropylmethyl bromide

LC-MS: rt=4.0 min, 531 (M+1, ES+).

EXAMPLE 265

[2-(Benzylcarbamoyl-methyl)-l-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-aceticacid ethyl ester:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith ethyl bromoacetate

LC-MS: rt=4.0 min.

EXAMPLE 266

2-[1-(3,4-dimethoxy-benzyl)-7-ethoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith ethyl iodide

LC-MS: rt=0.73 min, 531 (M+1, ES+).

EXAMPLE 267

2-[1-(3,4-dimethoxy-benzyl)-7-propoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith propyl bromide

LC-MS: rt=0.77 min, 545 (M+1, ES+).

EXAMPLE 268

2-[1-(3,4-dimethoxy-benzyl)-7-allyloxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith allyl bromide

LC-MS: rt=0.75 min, 543 (M+1, ES+).

EXAMPLE 269

2-[1-(3,4-dimethoxy-benzyl)-7-isopropoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith isopropyl bromide

LC-MS: rt=0.75 min, 545 (M+1, ES+).

EXAMPLE 270

2-[1-(3,4-dimethoxy-benzyl)-7-butoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith butyl bromide

LC-MS: rt=0.81 min, 559 (M+1, ES+).

EXAMPLE 271

2-[1-(3,4-dimethoxy-benzyl)-7-isobutoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith 1-bromo-2-methyl-propane

LC-MS: rt=0.80 min, 559 (M+1, ES+).

EXAMPLE 272

2-[1-(3,4-dimethoxy-benzyl)-7-(but-2-oxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith 2-bromo-butane

LC-MS: rt=0.78 min, 559 (M+1, ES+).

EXAMPLE 273

2-[1-(3,4-dimethoxy-benzyl)-7-(cyclopropyl-methoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith cyclopropyl-methyl bromide

LC-MS: rt=0.76 min, 557 (M+1, ES+).

EXAMPLE 274

2-[1-(3,4-dimethoxy-benzyl)-7-cyclohexyloxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith cyclohexyl bromide

LC-MS: rt=0.82 min, 585 (M+1, ES+).

EXAMPLE 275

[2-(Indan-1-ylcarbamoyl-methyl)-1-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydro-isoquinolin-7-yloxy]-aceticacid methyl ester:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith methyl bromoacetate

LC-MS: rt=0.70 min, 575 (M+1, ES+).

EXAMPLE 276

2-[1-(3,4-dimethoxy-benzyl)-7-(3-fluoro-propoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith 1-bromo-3-fluoro-propane

LC-MS: rt=0.74 min, 563 (M+1, ES+).

EXAMPLE 277

2-[1-(3,4-dimethoxy-benzyl)-7-(2-fluoro-ethoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith 1-bromo-2-fluoro-ethane

LC-MS: rt=0.72 min, 549 (M+1, ES+).

EXAMPLE 278

2-[1-(3,4-dimethoxy-benzyl)-7-(2,2-difluoro-ethoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith 1-bromo-2,2-difluoro-ethane

LC-MS: rt=0.75 min, 567 (M+1, ES+).

EXAMPLE 279

2-[1-(3,4-dimethoxy-benzyl)-5-ethoxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamidewith ethyl iodide

LC-MS: rt=0.61 min, 506 (M+1, ES+).

EXAMPLE 280

2-[1-(3,4-dimethoxy-benzyl)-5-propoxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamidewith propyl bromide

LC-MS: rt=0.66 min, 520 (M+1, ES+).

EXAMPLE 281

2-[1-(3,4-dimethoxy-benzyl)-5-allyloxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamidewith allyl bromide

LC-MS: rt=0.63 min, 518 (M+1, ES+).

EXAMPLE 282

2-[1-(3,4-dimethoxy-benzyl)-5-isopropoxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamidewith isopropyl bromide

LC-MS: rt=0.64 min, 520 (M+1, ES+).

EXAMPLE 283

2-[1-(3,4-dimethoxy-benzyl)-5-butoxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamidewith butyl bromide

LC-MS: rt=0.70 min, 534 (M+1, ES+).

EXAMPLE 284

2-[1-(3,4-dimethoxy-benzyl)-5-isobutoxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamidewith 1-bromo-2-methyl-propane

LC-MS: rt=0.70 min, 534 (M+1, ES+).

EXAMPLE 285

2-[1-(3,4-dimethoxy-benzyl)-5-(but-2-oxy)-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamidewith 2-bromo-butane

LC-MS: rt=0.68 min, 534 (M+1, ES+).

EXAMPLE 286

2-[1-(3,4-dimethoxy-benzyl)-5-(cyclopropyl-methoxy)-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamidewith cyclopropyl-methyl bromide

LC-MS: rt=0.66 min, 532 (M+1, ES+).

EXAMPLE 287

2-[1-(3,4-dimethoxy-benzyl)-5-(3-fluoro-propoxy)-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamidewith 1-bromo-3-fluoro-propane

LC-MS: rt=0.62 min, 538 (M+1, ES+).

EXAMPLE 288

2-[1-(3,4-dimethoxy-benzyl)-5-(2-fluoro-ethoxy)-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamidewith 1-bromo-2-fluoro-ethane

LC-MS: rt=0.59 min 524 (M+1, ES+).

EXAMPLE 289

2-[1-(3,4-dimethoxy-benzyl)-5-(2,2-difluoro-ethoxy)-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-pyridin-2-yl-methyl)-acetamidewith 1-bromo-2,2-difluoro-ethane

LC-MS: rt=0.61 m, 542 (M+1, ES+).

EXAMPLE 290

[2-[(Pyridin-2-yl-methyl)-carbamoyl-methyl]-1-(3,4-dimethoxy-benzyl)-8-methoxy-1,2,3,4-tetrahydro-isoquinolin-5-yloxy]-aceticacid methyl ester:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamidewith methyl bromoacetate

LC-MS: rt=0.58 min, 550 (M+1, ES+).

EXAMPLE 291

2-[1-(3,4-dimethoxy-benzyl)-8-ethoxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamidewith ethyl iodide

LC-MS: rt=0.62 min, 506 (M+1, ES+).

EXAMPLE 292

2-[1-(3,4-dimethoxy-benzyl)-8-propoxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamidewith propyl bromide

LC-MS: rt=0.66 min, 520 (M+1, ES+).

EXAMPLE 293

2-[1-(3,4-dimethoxy-benzyl)-8-allyloxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamidewith allyl bromide

LC-MS: rt=0.63 min, 518 (M+1, ES+).

EXAMPLE 294

2-[1-(3,4-dimethoxy-benzyl)-8-isopropoxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamidewith isopropyl bromide

LC-MS: rt=0.64 min, 520 (M+1, ES+).

EXAMPLE 295

2-[1-(3,4-dimethoxy-benzyl)-8-butoxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-pyridin-2-yl-methyl)-acetamidewith butyl bromide

LC-MS: rt=0.69 min, 534 (M+1, ES+).

EXAMPLE 296

2-[1-(3,4-dimethoxy-benzyl)-8-isobutoxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-pyridin-2-yl-methyl)-acetamidewith 1-bromo-2-methyl-propane

LC-MS: rt=0.69 min, 534 (M+1, ES+).

EXAMPLE 297

2-[1-(3,4-dimethoxy-benzyl)-8-(but-2-oxy)-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamidewith 2-bromo-butane

LC-MS: rt=0.68 min, 534 (M+1, ES+).

EXAMPLE 298

2-[1-(3,4-dimethoxy-benzyl)-8-(cyclopropyl-methoxy)-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamidewith cyclopropyl-methyl bromide

LC-MS: rt=0.66 min, 532 (M+1, ES+).

EXAMPLE 299

2-[1-(3,4-dimethoxy-benzyl)-8-cyclohexyloxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamidewith cyclohexyl bromide

LC-MS: rt=0.73 min, 560 (M+1, ES+).

EXAMPLE 300

2-[1-(3,4-dimethoxy-benzyl)-8-(3-fluoro-propoxy)-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamidewith 1-bromo-3-fluoro-propane

LC-MS: rt=0.62 min, 538 (M+1, ES+).

EXAMPLE 301

2-[1-(3,4-dimethoxy-benzyl)-8-(2-fluoro-ethoxy)-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamidewith 1-bromo-2-fluoro-ethane

LC-MS: rt=0.59 min, 524 (M+1, ES+).

EXAMPLE 302

2-[1-(3,4-dimethoxy-benzyl)-8-(2,2-difluoro-ethoxy)-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-pyridin-2-yl-methyl)-acetamidewith 1-bromo-2,2-difluoro-ethane

LC-MS: rt=0.62 min, 542 (M+1, ES+).

EXAMPLE 303

2-[1-(4-ethoxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith ethyl iodide

LC-MS: rt=3.9 min, 505 (M+1, ES+).

EXAMPLE 304

2-[1-(4-propoxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith propyl bromide

LC-MS: rt=4.2 min, 519 (M+1, ES+).

EXAMPLE 305

2-[1-(4-butoxy-3-methoxy-benzyl)6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith butyl bromide

LC-MS: rt=4.4 min, 533 (M+1, ES+).

EXAMPLE 306

2-[1-(4-allyloxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith allyl bromide

LC-MS: rt=4.0 min, 517 (M+1, ES+).

EXAMPLE 307

2-[1-(4-isopropoxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(4-hydroxy-3-methoxy-benzyl)6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith isopropyl bromide

LC-MS: rt=4.0 min. 519 (M+1, ES+).

EXAMPLE 308

2-[1-(4-isobutoxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith 1-bromo-2-methyl-propane

LC-MS: rt=4.5 min, 533 (M+1, ES+).

EXAMPLE 309

2-[1-(4-(cyclopropyl-methoxy)-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith cyclopropyl-methyl bromide

LC-MS: rt=4.2 min, 531 (M+1, ES+).

EXAMPLE 310

{4-[2-(Benzylcarbamoyl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl]-2-methoxy-phenoxy}-aceticacid ethyl ester

prepared by reaction of2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith ethyl bromoacetate

LC-MS: rt=3.9 min, 563 (M+1, ES+).

EXAMPLE 311

2-[1-(3-ethoxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith ethyl iodide

LC-MS: rt=3.8 min, 505 (M+1, ES+).

EXAMPLE 312

2-[1-(3-propoxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith propyl bromide

LC-MS: rt=4.1 min, 519 (M+1, ES+).

EXAMPLE 313

2-[1-(3-allyloxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith allyl bromide

LC-MS: rt=4.0 min, 517 (M+1, ES+).

EXAMPLE 314

2-[1-(3-isopropoxy-4-methoxy-benzyl)6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith isopropyl bromide

LC-MS: rt=4.0 min, 519 (M+1, ES+).

EXAMPLE 315

2-[1-(3-butoxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

prepared by reaction of2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith butyl bromide

LC-MS: rt=4.3 min, 533 (M+1, ES+).

EXAMPLE 316

2-{1-[3-(but-2-oxy)4-methoxy-benyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-N-benzyl-acetamide:

prepared by reaction of2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith 2-bromo-butane

LC-MS: rt=4.2 min, 533 (M+1, ES+).

EXAMPLE 317

2-{1-[3-(cyclopropyl-methoxy)-4-methoxy-benzyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-N-benzyl-acetamide:

prepared by reaction of2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith cyclopropyl-methyl bromide

LC-MS: rt=4.0 min, 531 (M+1, ES+).

EXAMPLE 318

2-{1-[3-(3-fluoro-propoxy)-4-methoxy-benzyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-N-benzyl-acetamide:

prepared by reaction of2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith 1-bromo-3-fluoro-propane

LC-MS: rt=3.9 min, 537 (M+1, ES+).

EXAMPLE 319

2-[1-(3,4-dimethoxy-benzyl)-7-(1-methyl-prop-2-oxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide:

At room temperature tert.-butyl 2,2,2-trichloroacetimidate (437 mg, 0.36mL, 2.0 mmol) was added to a solution of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide(95.3 mg, 0.2 mmol) in dichloromethane (5.0 mL) and cyclohexane (5.0mL). The reaction mixture was treated with a solution of borontrifluoride diethyl etherate (50 μL, 0.4 mmol) in 10 mL dichloromethaneand stirred for 22 h. Another portion of tert.-butyl2,2,2-trichloroacetimidate (244 mg, 0.20 mL, 1.1 mmol) was added. Afterstirring for three days a saturated solution of NaHCO₃ (10 mL), water(10 mL) and ethyl acetate (40 mL) were added, the phases were separatedand the aqueous phase was extracted three times with ethyl acetate (30mL). The combined organic phases were concentrated in vacuo and purifiedby flash-chromatography to give the titled product (80.4 mg, 75%) aspale yellow oil.

LC-MS: rt=4.2 min, 533 (M+1, ES+).

C.3 Reaktion of Phenols with Heteroaryl Chlorides or Heteroaryl-methylSulfones (General Procedure):

A solution of the respective heteroaryl chloride or methyl-sulfone inDMF (1.0 mL, 0.20 M) was added to a mixture of the respective phenol(0.15 mmol) and K₂CO₃ (75 mg). The reaction mixture was stirred at 100°C. for 16 h. Water (2.0 mL) and ethyl acetate (2.0 mL) were added, thephases were separated and the aqueous phase was extracted two times withethyl acetate. The combined organic phases were concentrated in vacuo togive the following tetrahydroisoquinoline derivatives:

EXAMPLE 320

2-{1-[3-(pyrimidin-2-yloxy)-4-methoxy-benzyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-N-benzyl-acetamide:

prepared by reaction of2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith 2-chloro-pyrimidine

LC-MS: rt=0.60 min, 555 (M+1, ES+).

EXAMPLE 321

2-{1-[4-(pyrimidin-2-yloxy)-3-methoxy-benzyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-N-benzyl-acetamide:

prepared by reaction of2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith 2-chloro-pyrimidine

LC-MS: rt=0.60 min, 555 (M+1, ES+).

EXAMPLE 322

2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-(pyrimidin-2-yloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith 2-chloro-pyrimidine

LC-MS: rt=3.81 min, 581 (M+1, ES+).

EXAMPLE 323

2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-(5-methoxy-pyrimidin-2-yloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith 2-methane-sulfonyl-5-methoxy-pyrimidine

LC-MS: rt=0.69 min, 611 (M+1, ES+).

EXAMPLE 324

2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-(4,6-dimethyl-pyrimidin-2-yloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith 2-methane-sulfonyl-4,6-dimethyl-pyrimidine

LC-MS: rt=0.70 min, 609 (M+1, ES+).

EXAMPLE 325

2-[1-(3,4-dimethoxy-benzyl-6-methoxy-7-(5-bromo-pyrimidin-2-yloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith 5-bromo-2-chloro-pyrimidine

LC-MS: rt=0.74 min, 659 (M+1, ES+).

EXAMPLE 326

2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-(5-methyl-pyrimidin-2-yloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith 2-chloro-5-methyl-pyrimidine

LC-MS: rt=0.68 min, 595 (M+1, ES+).

EXAMPLE 327

2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-(4,6-dimethoxy-pyrimidin-2-yloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith 2-methane-sulfonyl-4,6-dimethoxy-pyrimidine

LC-MS: rt=0.75 min, 641 (M+1, ES+).

EXAMPLE 328

2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-(5-trifluoromethyl-pyrimidin-2-yloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith 2-methane-sulfonyl-5-trifluoromethyl-pyrimidine

LC-MS: rt=0.77 min, 649 (M+1, ES+).

EXAMPLE 329

2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-(5-chloro-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith 2,5-dichloro-pyridine

LC-MS: rt=0.77 min, 614 (M+1, ES+).

EXAMPLE 330

2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-(5-trifluoromethyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith 2-chloro-5-trifluoromethyl-pyridine

LC-MS: rt=0.80 min, 648 (M+1, ES+).

EXAMPLE 331

2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-(4-trifluoromethyl-pyrimidin-2-yloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith 2-chloro-4-trifluoromethyl-pyrimidine

LC-MS: rt=0.77 min, 649 (M+1, ES+).

EXAMPLE 332

2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-(2,6-dimethoxy-pyrimidin-4-yloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith 4-chloro-2,6-dimethoxy-pyrimidine

LC-MS: rt=0.76 min, 641 (M+1, ES+).

EXAMPLE 333

2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-(pyrazin-2-yloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith 2-chloro-pyrazine

LC-MS: rt=0.68 min, 581 (M+1, ES+).

EXAMPLE 334

2-[1-(3,4-dimethoxy-benzyl)6-methoxy-7-(thiazol-2-yloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith 2-bromo-thiazole

LC-MS: rt=0.72 min, 586 (M+1, ES+).

C.4 Reaktion of Phenols with Carbamoylchlorides (General Procedure):

A solution of the respective phenol (0.20 mmol) and triethylamine (0.30mL, 2.15 mmol) in THF (1.0 mL) was treated with the respectivecarbamoylchloride (2.2 mmol) and stirred at reflux for 16 h. Water (2.0mL) and ethyl acetate (2.0 mL) were added, the phases were separated andthe aqueous phase was extracted two times with ethyl acetate. Thecombined organic phases were concentrated in vacuo to give the followingtetrahydroisoquinoline derivatives:

EXAMPLE 335

2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-(N,N-dimethylcarbamoyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith N,N-dimethylcarbamoyl chloride

LC-MS: rt=0.74 min, 574 (M+1, ES+).

EXAMPLE 336

2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-(4-morpholine-carbonyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamidewith 4-morpholinecarbonyl chloride

LC-MS: rt=0.72 min, 616 (M+1, ES+).

EXAMPLE 337

2-{1-[4-Methoxy-3-(N,N-dimethylcarbamoyloxy)-benzyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-N-benzyl-acetamide:

prepared by reaction of2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith N,N-dimethyl-carbamoyl chloride

LC-MS: rt=0.62 min, 548 (M+1, ES+).

EXAMPLE 338

2-{1-[3-Methoxy-4-(N,N-dimethylcarbamoyloxy)-benzyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-N-benzyl-acetamide:

prepared by reaction of2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith N,N-dimethyl-carbamoyl chloride

LC-MS: rt=0.63 min, 548 (M+1, ES+).

EXAMPLE 339

2-{1-[3-Methoxy-4-(4-morpholine-carbonyloxy)-benzyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-N-benzyl-acetamide:

prepared by reaction of2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamidewith 4-morpholine-carbonyl chloride

LC-MS: rt=0.61 min, 590 (M+1, ES+).

D Coupling of 1-Hydroxymethyl-Substituted Tetrahydroisoquinolines withNitrogen-Nucleophiles (General Procedure):

To a solution of2-(1-Hydroxymethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(indan-1-yl)-acetamide(0.10 mmol) and diisopropylethyl-amine (0.25 mmol) in THF (0.50 mL) wasadded a solution of methanesulfonyl chloride in THF (0.25 mL, 0.44 M).After 60 min the reaction mixture was treated with a solution of therespective nitrogen-nucleophile in THF (0.25 mL, 0.48 M) and stirred for18 h. Water (2.0 mL) and ethyl acetate (2.0 mL) were added, the phaseswere separated and the aqueous phase was extracted two times with ethylacetate. The combined organic phases were concentrated in vacuo to givethe following tetrahydroisoquinoline derivatives:

EXAMPLE 340

2-[1-(5,6-Dimethyl-benzoimidazol-1-ylmethyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-(1-Hydroxymethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(indan-1-yl)-acetamidewith 5,6-dimethylbenzimidazole

LC-MS: rt=0.64 min 525 (M+1, ES+).

EXAMPLE 341

2-[1-(1,2,3,4-Tetrahydroisoquinolin-2-ylmethyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide:

prepared by reaction of2-(1-Hydroxymethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(indan-1-yl)-acetamidewith 1,2,3,4-tetrahydro-isoquinoline

LC-MS: rt=0.71 min, 512 (M+1, ES+).

E. General Procedure for the Preparation of the Isonitrile Derivatives

Isonitriles (or isocyanides) have been prepared by reaction of theN-alkyl-formamides (formed by reaction of the corresponding amine withformic ethyl ester) with POCl₃.

ABBREVIATIONS

BSA Bovine serum albumine

CHO Chinese hamster ovary

DMF Dimethylformamide

DMSO Dimethylsulfoxide

ES Electron spray

FCS Foetal calf serum

FLIPR Fluorescent imaging plate reader

HBSS Hank's balanced salt solution

HEPES 4-(2-Hydroxyethyl)-piperazine-1-ethanesulfonic acid

MeOH Methanol

MS Mass spectroscopy

LC Liquid chromatography

PyBOPBenzotriazole-1-yl-oxy-tris-pyrrolidino-Phosphoniumhexafluorophosphate

R_(f) Retention front

R_(t) retention time

RT Room temperature

THF Tetrahydrofuran

What is claimed is:
 1. A compound of formula (I):

wherein: R¹, R², R³, R⁴ independently represent cyano, nitro, halogen,hydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, loweralkenyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyloxy, aryloxy,aralkyloxy, heterocyclyloxy, heterocyclylalkyloxy, R¹¹CO—, NR¹²R¹³CO—,R¹²R¹³N—, R¹¹OOC—, R¹¹SO₂NH— or R¹⁴—CO—NH—, or R² and R³ together aswell as R¹ and R² together and R³ and R⁴ together may form with thephenyl ring a five, six or seven-membered ring containing one or twooxygen atoms; R⁵ represents aryl, aralkyl, lower alkenyl,trifluoromethyl, cycloalkyl, heterocyclyl or heterocyclyl-lower alkyl;R⁶ represents hydrogen, aryl, aralkyl, lower alkyl, lower alkenyl,trifluoromethyl, cycloalkyl, heterocyclyl or heterocyclyl-lower alkyl;R⁷ and R⁸ independently represent hydrogen, aryl, aralkyl, lower alkyl,lower alkenyl, cycloalkyl, heterocyclyl or heterocyclyl-lower alkyl; R⁹represents aryl, aralkyl, lower alkyl, lower alkenyl, trifluoromethyl,cycloalkyl, heterocyclyl or heterocyclyl-lower alkyl; R¹⁰ representshydrogen, aryl, aralkyl, lower alkyl, lower alkenyl, trifluoromethyl,cycloalkyl, heterocyclyl or heterocyclyl-lower alkyl; R¹¹ representslower alkyl, aryl, aralkyl, heterocyclyl or heterocyclyl-lower alkyl;R¹² and R¹³ independently represent hydrogen, alkyl, cycloalkyl, aryl,aralkyl, heterocyclyl or heterocyclyl-lower alkyl; and R¹⁴ representsalkyl, aryl, cycloalkyl, heterocyclyl, R¹²R¹³N— or R¹¹O—, includingoptically pure enantiomers, mixtures of enantiomers, racemates,optically pure diastereoisomers, mixtures of diastereoisomers,diastereoisomeric racemates, mixtures of diastereolsomeric racemates,meso forms, and pharmaceutically acceptable salts thereof.
 2. A compoundof formula (II)

wherein: R′¹ and R′² independently represent hydrogen, hydroxy, loweralkoxy or halogen or may form with the phenyl ring a five, six or sevenmembered-ring containing one or two oxygen atoms; R′³ represents aryl,aralkyl, lower alkenyl, cycloalkyl, heterocyclyl or heterocyclyl-loweralkyl; R′⁴ represents hydrogen, aryl, aralkyl, lower alkyl, loweralkenyl, cycloalkyl, heterocyclyl or heterocyclyl-lower alkyl; and R′⁵represents aryl, aralkyl, lower alkyl, lower alkenyl, cycloalkyl,heterocyclyl or heterocyclyl-lower alkyl; including optically pureenantiomers, mixtures of enantiomers, racemates, optically purediastereoisomers, mixtures of diastercoisomers, diastercoisomericracemates, mixtures of diastereoisomeric racemates, meso forms, andpharmaceutically acceptable salts thereof.
 3. A compound selected from:2-[1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide;2-[1-(3,4-dimethoxy-benzyl)-8-(cyclopropyl-methoxy)-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide;2-[1-(3,4-dimethoxy-benzyl)-8-(2-fluoro-ethoxy)-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide;2-[1-(3,4-dimethoxy-benzyl)-8-(2,2-difluoro-ethoxy)-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide;2-[1-(3,4-dimethoxy-benzyl)-8-ethoxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide;2-[1-(3,4-dimethoxy-benzyl)-8-propoxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide;2-[1-(3,4-dimethoxy-benzyl)-8-allyloxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide;2-[1-(3,4-dimethoxy-benzyl)-8-isopropoxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide;2-[1-(3,4-dimethoxy-benzyl)-5-propoxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-naphthalen-1-yl-methyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide;2-[1-(3,4-Dimethoxy-benzyl)6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide;2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-(pyrazin-2-yloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide;2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7(thiazol-2-yloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide;2-[l-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(5-methoxy-indan-1-yl)-acetamide;2-[1-(3,4-Dimethoxy-benzyl]-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(6-methoxy-indan-1-yl)-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(6-methyl-indan-1-yl)-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(4-methyl-indan-1-yl)-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-6-methoxy-indan-1-yl)-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]N-(6-methyl-indan-1-yl)-acetamide;2-{1-[4-(pyrimidin-2-yloxy)-3-methoxy-benzyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl}-N-benzyl-acetamide;2-[1-(3,4-dimethoxy-benzyl)-6-methoxy-7-(N,N-dimethylcarbamoyloxy)-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide;2-[1-(3,4-dimethoxy-benzyl)-7-(3-fluoro-propoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide;2-[1-(3,4-dimethoxy-benzyl)-7-(2-fluoro-ethoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide;2-[1-(3,4-dimethoxy-benzyl)-7(2,2-difluoro-ethoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan1-yl)-acetamide;2-[1-(3,4-dimethoxy-benzyl)-7-(but-2-oxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide;2-[1-(3,4-dimethoxy-benzyl]-7(cyclopropyl-methoxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan1-yl)-acetamide;2-[1-(3,4-dimethoxy-benzyl)-7-ethoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide;2-[1-(3,4-dimethoxy-benzyl)-7-propoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide;2-[1-(3,4-dimethoxy-benzyl)-7-allyloxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide;2-[1-(3,4-dimethoxy-benzyl)-7-isopropoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide;2-[1-(3,4-dimethoxy-benzyl)-7-(1-methyl-prop-2-oxy)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1S)-indan-1-yl]-acetamide;2-[1-(3,4-Dimethoxy-benzyl)-6-methoxy-7isopropoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide;2-[(1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1S)-indan-1-yl]-acetamide;2-[1-(3,4-dimethoxy-benzyl)-7-ethoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide;2-[1-(3,4-dimethoxy-benzyl)-7-propoxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide;2-[1-(3,4-dimethoxy-benzyl)-7-allyloxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide;N-benzyl-2-[1-(3,4-Dimethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-acetamide;2-[1-(3,4-Dimethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-[(1S)-indan-1-yl]-acetamide;N-benzyl-2-[1-(3,4-Diethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-acetamide;2-[1-(3,4-Diethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide;2-[1-(3,4-Diethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-3-yl-methyl)-acetamide;2-[1-(3,4-Diethyl-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-4-yl-methyl)-acetamide;or2-[1-(3,4-Dichloro-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-3-yl-methyl)-acetamide.4. A process for the combinatorial preparation of a compound of formula(I) of claim 1, wherein R⁶, R⁷ and R⁹ are hydrogen, using anUgi-three-components-condensation reaction, comprising one pot reactionof a compound of formula (III):

wherein R₁, R₂, R₃, R₄ and R₅ are as defined in formula (I) of claim 1and R₆ represents hydrogen, with a compound of formula (IV):

wherein R₇ represents hydrogen and R₈ is as defined in formula (I) ofclaim 1, and a compound of formula (V):

wherein R₁₀ is as defined in formula (I) of claim 1, optionallyisolating a pharmacologically active compound, optionally resolving aracemate and, optionally converting a compound obtained into a salt. 5.A process for the preparation of a compound of formula (I) of claim 1,comprising reacting a compound of formula (III′):

wherein the substituents R₁ to R₆ are as defined in formula (I) of claim1, with a compound of formula (VI):

wherein R₇ to R₁₀ are as defined in formula (I) of claim
 1. 6. A processfor the preparation of a compound of formula (I) of claim 1, comprisingreacting a compound of formula (III′):

wherein the substituents R₁ to R₆ are as defined in formula (I) of claim1, with a) a compound of formula (IX):

wherein R₇, R₈ and R₁₁ are as defined in formula (I) of claim 1, b)cleaving an ester and reacting the acid formed with c) a compound offormula (X):

wherein the substituents R₉ and R₁₀ are as defined in formula (I) ofclaim 1, optionally resolving a racemate and, optionally converting acompound obtained into a salt.
 7. A pharmaceutical compositioncomprising the compound of claim 1, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier and/or adjuvant.8. A method of treating a subject with a disorder which is associatedwith a role of orexin, comprising administering the compound of claim 1,or a pharmaceutically acceptable salt thereof.
 9. A method of treatingor preventing a disease or disorder where an antagonist of a humanorexin receptor is required, comprising administering to a subject inneed thereof an effective amount of the compound of claim 1, or apharmaceutically acceptable salt thereof.
 10. A process for themanufacture of a pharmaceutical composition which comprises a compoundof claim 1, or a pharmaceutically acceptable salt thereof, as an activeingredient, comprising mixing one or more active ingredient oringredients with a pharmaceutically acceptable excipient and/oradjuvant.
 11. The method according to claim 8, wherein the disorder isobesity or a sleep disorder.
 12. A compound of claim 1 that is2-[1-(3,4-dimethoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)acetamide.
 13. A pharmaceutical composition comprising the compound ofclaim 2, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier and/or adjuvant.
 14. A method oftreating a subject with a disorder which is associated with a role oforexin, comprising administering the compound of claim 2, or apharmaceutically acceptable salt thereof.
 15. A method of treating orpreventing a disease or disorder where an antagonist of a human orexinreceptor is required, comprising administering to a subject in needthereof an effective amount of the compound of claim 2, or apharmaceutically acceptable salt thereof.
 16. A process for themanufacture of a pharmaceutical composition which comprises a compoundof claim 2, or a pharmaceutically acceptable salt thereof, as an activeingredient, comprising mixing one or more active ingredient oringredients with a pharmaceutically acceptable excipient and/oradjuvant.
 17. The method of claim 14, wherein the disorder is obesity ora sleep disorder.
 18. A pharmaceutical composition comprising thecompound of claim 3, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier and/or adjuvant.
 19. A method oftreating a subject with a disorder which is associated with a role oforexin, comprising administering the compound of claim 3, or apharmaceutically acceptable salt thereof.
 20. A method of treating orpreventing a disease or disorder where an antagonist of a human orexinreceptor is required, comprising administering to a subject in needthereof an effective amount of the compound of claim 3, or apharmaceutically acceptable salt thereof.
 21. A process for themanufacture of a pharmaceutical composition which comprises a compoundof claim 3, or a pharmaceutically acceptable salt thereof, as an activeingredient, comprising mixing one or more active ingredient oringredients with a pharmaceutically acceptable excipient and/oradjuvant.
 22. The method of claim 19, wherein the disorder is obesity ora sleep disorder.